Pharmaceuticals for the imaging of angiogenic disorders

ABSTRACT

The present invention describes novel compounds of the formula: 
     
       
         (Q) d —L n —C h , 
       
     
     useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient. The present invention also provides novel compounds useful for monitoring therapeutic angiogenesis treatment and destruction of new angiogenic vasculature. The pharmaceuticals are comprised of a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.

This is a continuation-in-part of application Ser. No. 09/281,474, filedMar. 30, 1999, which is now pending, which in turn claims the benefit ofU.S. Provisional Application No. 60/080,150 filed Mar. 31, 1998 andProvisional Application No. 60/112,715, filed Dec. 18, 1998.

FIELD OF THE INVENTION

The present invention provides novel pharmaceuticals useful for thediagnosis and treatment of cancer, methods of imaging tumors in apatient, and methods of treating cancer in a patient. The invention isalso directed to novel pharmaceutical compositions and combinationtherapy comprising a compound of the invention or a pharmaceuticallyacceptable salt thereof, and at least one agent selected from the groupconsisting of a chemotherapeutic agent and a radiosensitizer agent. Thepresent invention also provides novel pharmaceuticals useful formonitoring therapeutic angiogenesis treatment and destruction of newangiogenic vasculature. The pharmaceuticals are comprised of a targetingmoiety that binds to a receptor that is upregulated during angiogenesis,an optional linking group, and a therapeutically effective radioisotopeor diagnostically effective imageable moiety. The therapeuticallyeffective radioisotope emits a particle or electron sufficient to becytotoxic. The imageable moiety is a gamma ray or positron emittingradioisotope, a magnetic resonance imaging contrast agent, an X-raycontrast agent, or an ultrasound contrast agent.

BACKGROUND OF THE INVENTION

Cancer is a major public health concern in the United States and aroundthe world. It is estimated that over 1 million new cases of invasivecancer will be diagnosed in the United States in 1998. The mostprevalent forms of the disease are solid tumors of the lung, breast,prostate, colon and rectum. Cancer is typically diagnosed by acombination of in vitro tests and imaging procedures. The imagingprocedures include X-ray computed tomography, magnetic resonanceimaging, ultrasound imaging and radionuclide scintigraphy. Frequently, acontrast agent is administered to the patient to enhance the imageobtained by X-ray CT, MRI and ultrasound, and the administration of aradiopharmaceutical that localizes in tumors is required forradionuclide scintigraphy.

Treatment of cancer typically involves the use of external beamradiation therapy and chemotherapy, either alone or in combination,depending on the type and extent of the disease. A number ofchemotherapeutic agents are available, but generally they all sufferfrom a lack of specificity for tumors versus normal tissues, resultingin considerable side-effects. The effectiveness of these treatmentmodalities is also limited, as evidenced by the high mortality rates fora number of cancer types, especially the more prevalent solid tumordiseases. More effective and specific treatment means continue to beneeded.

Despite the variety of imaging procedures available for the diagnosis ofcancer, there remains a need for improved methods. In particular,methods that can better differentiate between cancer and otherpathologic conditions or benign physiologic abnormalities are needed.One means of achieving this desired improvement would be to administerto the patient a metallopharmaceutical that localizes specifically inthe tumor by binding to a receptor expressed only in tumors or expressedto a significantly greater extent in tumors than in other tissue. Thelocation of the metallopharmaceutical could then be detected externallyeither by its imageable emission in the case of certainradiopharmaceuticals or by its effect on the relaxation rate of water inthe immediate vicinity in the case of magnetic resonance imagingcontrast agents.

This tumor specific metallopharmaceutical approach can also be used forthe treatment of cancer when the metallopharmaceutical is comprised of aparticle emitting radioisotope. The radioactive decay of the isotope atthe site of the tumor results in sufficient ionizing radiation to betoxic to the tumor cells. The specificity of this approach for tumorsminimizes the amount of normal tissue that is exposed to the cytotoxicagent and thus may provide more effective treatment with fewerside-effects.

Previous efforts to achieve these desired improvements in cancer imagingand treatment have centered on the use of radionuclide labeledmonoclonal antibodies, antibody fragments and other proteins orpolypeptides (i.e., molecular weight over 10,000 D) that bind to tumorcell surface receptors. The specificity of these radiopharmaceuticals isfrequently very high, but they suffer from several disadvantages. First,because of their high molecular weight, they are generally cleared fromthe blood stream very slowly, resulting in a prolonged blood backgroundin the images. Also, due to their molecular weight they do notextravasate readily at the site of the tumor and then only slowlydiffuse through the extravascular space to the tumor cell surface. Thisresults in a very limited amount of the radiopharmaceutical reaching thereceptors and thus very low signal intensity in imaging and insufficientcytotoxic effect for treatment.

Alternative approaches to cancer imaging and therapy have involved theuse of small molecules, such as peptides, that bind to tumor cellsurface receptors. An ¹¹¹In labeled somatostatin receptor bindingpeptide, ¹¹¹In-DTPA-D-Phe¹-octeotide, is in clinical use in manycountries for imaging tumors that express the somatostatin receptor(Baker, et al., Life Sci., 1991, 49, 1583-91 and Krenning, et al., Eur.J. Nucl. Med., 1993, 20, 716-31). Higher doses of thisradiopharmaceutical have been investigated for potential treatment ofthese types of cancer (Krenning, et al., Digestion, 1996, 57, 57-61).Several groups are investigating the use of Tc-99m labeled analogs of¹¹¹In-DTPA-D-Phe¹-octeotide for imaging and Re-186 labeled analogs fortherapy (Flanagan, et al., U.S. Pat. No. 5,556,939, Lyle, et al., U.S.Pat. No. 5,382,654, and Albert et al., U.S. Pat. No. 5,650,134).

Angiogenesis is the process by which new blood vessels are formed frompre-existing capillaries or post capillary venules; it is an importantcomponent of a variety of physiological processes including ovulation,embryonic development, wound repair, and collateral vascular generationin the myocardium. It is also central to a number of pathologicalconditions such as tumor growth and metastasis, diabetic retinopathy,and macular degeneration. The process begins with the activation ofexisting vascular endothelial cells in response to a variety ofcytokines and growth factors. Tumor released cytokines or angiogenicfactors stimulate vascular endothelial cells by interacting withspecific cell surface receptors for the factors. The activatedendothelial cells secrete enzymes that degrade the basement membrane ofthe vessels. The endothelial cells then proliferate and invade into thetumor tissue. The endothelial cells differentiate to form lumens, makingnew vessel offshoots of pre-existing vessels. The new blood vessels thenprovide nutrients to the tumor permitting further growth and a route formetastasis.

Under normal conditions, endothelial cell proliferation is a very slowprocess, but it increases for a short period of time duringembryogenesis, ovulation and wound healing. This temporary increase incell turnover is governed by a combination of a number of growthstimulatory factors and growth suppressing factors. In pathologicalangiogenesis, this normal balance is disrupted resulting in continuedincreased endothelial cell proliferation. Some of the pro-angiogenicfactors that have been identified include basic fibroblast growth factor(bFGF), angiogenin, TGF-alpha, TGF-beta, and vascular endothelium growthfactor (VEGF), while interferon-alpha, interferon-beta andthrombospondin are examples of angiogenesis suppressors.

The proliferation and migration of endothelial cells in theextracellular matrix is mediated by interaction with a variety of celladhesion molecules (Folkman, J., Nature Medicine, 1995, 1, 27-31).Integrins are a diverse family of heterodimeric cell surface receptorsby which endothelial cells attach to the extracellular matrix, eachother and other cells. The integrin α_(v)β₃ is a receptor for a widevariety of extracellular matrix proteins with an exposed tripeptideArg-Gly-Asp moiety and mediates cellular adhesion to its ligands:vitronectin, fibronectin, and fibrinogen, among others. The integrinα_(v)β₃ is minimally expressed on normal blood vessels, but, issignificantly upregulated on vascular cells within a variety of humantumors. The role of the α_(v)β₃ receptors is to mediate the interactionof the endothelial cells and the extracellular matrix and facilitate themigration of the cells in the direction of the angiogenic signal, thetumor cell population. Angiogenesis induced by bFGF or TNF-alpha dependon the agency of the integrin α_(v)β₃, while angiogenesis induced byVEGF depends on the integrin α_(v)β₅ (Cheresh et. al., Science, 1995,270, 1500-2). Induction of expression of the integrins α₁β₁ and α₂β₁ onthe endothelial cell surface is another important mechanism by whichVEGF promotes angiogenesis (Senger, et. al., Proc. Natl. Acad, Sci USA,1997, 94, 13612-7).

Angiogenic factors interact with endothelial cell surface receptors suchas the receptor tyrosine kinases EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1,Tek, Tie, neuropilin-1, endoglin, endosialin, and Axl. The receptorsFlk-1/KDR, neuropilin-1, and Flt-1 recognize VEGF and these interactionsplay key roles in VEGF-induced angiogenesis. The Tie subfamily ofreceptor tyrosine kinases are also expressed prominently during bloodvessel formation.

Because of the importance of angiogenesis to tumor growth andmetastasis, a number of chemotherapeutic approaches are being developedto interfere with or prevent this process. One of these approaches,involves the use of anti-angiogenic proteins such as angiostatin andendostatin. Angiostatin is a 38 kDa fragment of plasminogen that hasbeen shown in animal models to be a potent inhibitor of endothelial cellproliferation. (O'Reilly et. al., Cell, 1994, 79, 315-328) Endostatin isa 20 kDa C-terminal fragment of collagen XVIII that has also been shownto be a potent inhibitor. (O'Reilly et. al., Cell, 1997, 88, 277-285)

Systemic therapy with endostatin has been shown to result in stronganti-tumor activity in animal models.

However, human clinical trials of these two chemotherapeutic agents ofbiological origin have been hampered by lack of availability.

Another approach to anti-angiogenic therapy is to use targeting moietiesthat interact with endothelial cell surface receptors expressed in theangiogenic vasculature to which are attached chemotherapeutic agents.Burrows and Thorpe (Proc. Nat. Acad. Sci, USA, 1993, 90, 8996-9000)described the use of an antibody-immunotoxin conjugate to eradicatetumors in a mouse model by destroying the tumor vasculature. Theantibody was raised against an endothelial cell class II antigen of themajor histocompatibility complex and was then conjugated with thecytotoxic agent, deglycosylated ricin A chain. The same group (Clin.Can. Res., 1995, 1, 1623-1634) investigated the use of antibodies raisedagainst the endothelial cell surface receptor, endoglin, conjugated todeglycosylated ricin A chain. Both of these conjugates exhibited potentanti-tumor activity in mouse models. However, both still sufferdrawbacks to routine human use. As with most antibodies or other large,foreign proteins, there is considerable risk of immunologic toxicitywhich could limit or preclude administration to humans. Also, while thevasculature targeting may improve the local concentration of theattached chemotherapeutic agents, the agents still must be cleaved fromthe antibody carrier and be transported or diffuse into the cells to becytotoxic.

Thus, it is desirable to provide anti-angiogenic pharmaceuticals andtumor or new vasculature imaging agents which don't suffer from poordiffusion or transportation, possible immunologic toxicity, limitedavailability, and/or a lack of specificity.

There continues to be a need for more effective treatment options forpatients with solid tumors. This is especially true in cases ofmetastatic cancer in which current standard chemotherapy and externalbeam radiation regimens only result in marginal survival improvements.

Although improvements in cytotoxic chemotherapeutics have been made inrecent years, the toxicity of these compounds to normal tissues hascontinued to severely limit their utility in extending survival inpatients with solid tumors. Recently developed combinations of differenttherapeutic modalities, such as external beam irradiation andchemotherapy (i.e. chemoradiation), has provided some incrementalbenefit to the control of tumor progression and quality of life.However, neither systemic chemotherapeutics nor external beamirradiation have acceptable therapeutic indices, and are often limiteddue to unacceptable toxicity to normal tissues. The concept of combinedtherapy of cancer using anti-angiogenesis drugs in combination withchemotherapeutics is not new. Further, the concept of combining targetedin-vivo radiotherapy using radiolabeled antibodies and antibodyfragments with chemotherapy has been reported (Stein R, Juweid M, ZhangC, et al., Clin. Cancer Res., 5: 3199s-3206s, 1999. However, thecombination of a angiogenesis-targeted therapeutic radiopharmaceuticalwhich is targeted to receptors, which are then upregulated in theneovasculature of tumors, together with chemotherapy has not beendescribed before. Therefore, there is a need for a combination of atherapeutic radiopharmaceutical, which is targeted to localize in theneovasculature of tumors, with chemotherapeutics or a radiosensitizeragent, or a pharmaceutically acceptable salt thereof, to provideadditive or synergistic therapeutic response without unacceptableadditive toxicity in the treatment of solid tumors.

The major advantage of combined chemotherapy and angiogenesis-targetedtherapeutic radiopharmaceuticals, over each therapeutic modality alone,is improved tumor response without substantial increases in toxicityover either treatment alone. The advantage of using neovascular-specificradiopharmaceuticals, versus a tumor-cell targeted antibody, is thatthere is much lower systemic radiation exposure to the subject beingtreated.

Further, if the receptor targets for the radiopharmaceutical compounds,used in this method of treatment, are expressed on the luminal side oftumor vessels, there is no requirement that these compounds traverse thecapillary bed and bind to the tumor itself.

Thus, it is desirable to provide a combination of angiogenesis-targetedtherapeutic radiopharmaceuticals and a chemotherapeutics or aradiosensitizer agent, or a pharmaceutically acceptable salt thereof,which target the luminal side of the neovasculature of tumors, toprovide a surprising, and enhanced degree of tumor suppression relativeto each treatment modality alone without significant additive toxicity.

There is also a growing interest in therapeutic angiogenesis to improveblood flow in regions of the body that have become ischemic or poorlyperfused. Several investigators are using growth factors administeredlocally to cause new vasculature to form either in the limbs or theheart. The growth factors VEGF and bFGF are the most common for thisapplication. Recent publications include: Takeshita, S., et. al., J.Clin. Invest., 1994, 93, 662-670; and Schaper, W. and Schaper, J.,Collateral Circulation:Heart, Brain, Kidney, Limbs, Kluwer AcademicPublishers, Boston, 1993. The main applications that are underinvestigation in a number of laboratories are for improving cardiacblood flow and in improving peripheral vessal blood flow in the limbs.For example, Henry, T. et. al. (J. Amer. College Cardiology, 1998, 31,65A) describe the use of recombinant human VEGF in patients forimproving myocardial perfusion by therapeutic angiogenesis. Patientsreceived infusions of rhVEGF and were monitored by nuclear perfusionimaging 30 and 60 days post treatment to determine improvement inmyocardial perfusion. About 50% of patients showed improvement bynuclear perfusion imaging whereas 5/7 showed new collatoralization byangiography.

Thus, it is desirable to discover a method of monitoring improvedcardiac blood flow which is targeted to new collateral vesselsthemselves and not, as in nuclear perfusion imaging, a regionalconsequence of new collateral vessels.

SUMMARY OF THE INVENTION

It is one object of the present invention to provide anti-angiogenicpharmaceuticals, comprised of a targeting moiety that binds to areceptor that is expressed in tumor neovasculature, an optional linkinggroup, and a radioactive metal ion that emits ionizing radiation such asbeta particles, alpha particles and Auger or Coster-Kronig electrons.The receptor binding compounds target the radioisotope to the tumorneovasculature. The beta or alpha-particle emitting radioisotope emits acytotoxic amount of ionizing radiation which results in cell death. Thepenetrating ability of radiation obviates the requirement that thecytotoxic agent diffuse or be transported into the cell to be cytotoxic.

It is another object of the present invention to provide pharmaceuticalsto treat rheumatoid arthritis. These pharmaceuticals comprise atargeting moiety that binds to a receptor that is upregulated duringangiogenesis, an optional linking group, and a radioisotope that emitscytotoxic radiation (i.e., beta particles, alpha particles and Auger orCoster-Kronig electrons). In rheumatoid arthritis, the ingrowth of ahighly vascularized pannus is caused by the excessive production ofangiogenic factors by the infiltrating macrophages, immune cells, orinflammatory cells. Therefore, the radiopharmaceuticals of the presentinvention that emit cytotoxic radiation could be used to destroy the newangiogenic vasculature that results and thus treat the disease.

It is another object of the present invention to provide tumor imagingagents, comprised of targeting moiety that binds to a receptor that isupregulated during angiogenesis, an optional linking group, and animageable moiety, such as a gamma ray or positron emitting radioisotope,a magnetic resonance imaging contrast agent, an X-ray contrast agent, oran ultrasound contrast agent.

It is another object of the present invention to provide imaging agentsfor monitoring the progress and results of therapeutic angiogenesistreatment. These agents comprise of targeting moiety that binds to areceptor that is upregulated during angiogenesis, an optional linkinggroup, and an imageable moiety. Imaging agents of the present inventioncould be administered intravenously periodically after theadministration of growth factors and imaging would be performed usingstandard techniques of the affected areas, heart or limbs, to monitorthe progress and results of the therapeutic angiogenesis treatment(i.e., image the formation of new blood vessels).

It is another object of the present invention to provide compoundsuseful for preparing the pharmaceuticals of the present invention. Thesecompounds are comprised of a peptide or peptidomimetic targeting moietythat binds to a receptor that is upregulated during angiogenesis, Q, anoptional linking group, L_(n), and a metal chelator or bonding moiety,C_(h). The compounds may have one or more protecting groups attached tothe metal chelator or bonding moiety. The protecting groups provideimproved stability to the reagents for long-term storage and are removedeither immediately prior to or concurrent with the synthesis of theradiopharmaceuticals. Alternatively, the compounds of the presentinvention are comprised of a peptide or peptidomimetic targeting moietythat binds to a receptor that is upregulated during angiogenesis, Q, anoptional linking group, L_(n), and a surfactant, S_(f).

The pharmaceuticals of the present invention may be used for diagnosticand/or therapeutic purposes. Diagnostic radiopharmaceuticals of thepresent invention are pharmaceuticals comprised of a diagnosticallyuseful radionuclide (i.e., a radioactive metal ion that has imageablegamma ray or positron emissions). Therapeutic radiopharmaceuticals ofthe present invention are pharmaceuticals comprised of a therapeuticallyuseful radionuclide, a radioactive metal ion that emits ionizingradiation such as beta particles, alpha particles and Auger orCoster-Kronig electrons.

The pharmaceuticals comprising a gamma ray or positron emittingradioactive metal ion are useful for imaging tumors by gammascintigraphy or positron emission tomography. The pharmaceuticalscomprising a gamma ray or positron emitting radioactive metal ion arealso useful for imaging therapeutic angiogenesis by gamma scintigraphyor positron emission tomography. The pharmaceuticals comprising aparticle emitting radioactive metal ion are useful for treating cancerby delivering a cytotoxic dose of radiation to the tumors. Thepharmaceuticals comprising a particle emitting radioactive metal ion arealso useful for treating rheumatoid arthritis by destroying theformation of angiogenic vasculature. The pharmaceuticals comprising aparamagnetic metal ion are useful as magnetic resonance imaging contrastagents. The pharmaceuticals comprising one or more X-ray absorbing or“heavy” atoms of atomic number 20 or greater are useful as X-raycontrast agents. The pharmaceuticals comprising a microbubble of abiocompatible gas, a liquid carrier, and a surfactant microsphere, areuseful as ultrasound contrast agents.

DETAILED DESCRIPTION OF THE INVENTION

[1] Thus, in a first embodiment, the present invention provides a novelcompound, comprising: a targeting moiety and a chelator, wherein thetargeting moiety is bound to the chelator, is a peptide orpeptidomimetic, and binds to a receptor that is upregulated duringangiogenesis and the compound has 0-1 linking groups between thetargeting moiety and chelator.

[2] In a preferred embodiment, the targeting moiety is a peptide or amimetic thereof and the receptor is selected from the group: EGFR, FGFR,PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin,Axl, α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁, α₁β₁, and α₂β₂ and the linking groupis present between the targeting moiety and chelator.

[3] In a more preferred embodiment, the receptor is the integrin α_(v)β₃and the compound is of the formula:

(Q)_(d)—L_(n)—C_(h) or (Q)_(d)—L_(n)—(C_(h))_(d′)

wherein, Q is a peptide independently selected from the group:

K is an L-amino acid independently selected at each occurrence from thegroup: arginine, citrulline, N-methylarginine, lysine, homolysine,2-aminoethylcysteine, δ-N-2-imidazolinylornithine,δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid;

K′ is a D-amino acid independently selected at each occurrence from thegroup: arginine, citrulline, N-methylarginine, lysine, homolysine,2-aminoethylcysteine, δ-N-2-imidazolinylornithine,δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid;

L is independently selected at each occurrence from the group: glycine,L-alanine, and D-alanine;

M is L-aspartic acid;

M′ is D-aspartic acid;

R¹ is an amino acid substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, L-valine, D-valine,alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid,2-aminohexanoic acid, tyrosine, phenylalanine, thienylalanine,phenylglycine, cyclohexylalanine, homophenylalanine, 1-naphthylalanine,lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionicacid, cysteine, penicillamine, and methionine;

R² is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, valine, alanine,leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoicacid, tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine,phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine,L-1-naphthylalanine, D-1-naphthylalanine, lysine, serine, ornithine,1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine,penicillamine, methionine, and 2-aminothiazole-4-acetic acid;

R³ is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, D-valine,D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine,D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine,D-1-naphthylalanine, D-lysine, D-serine, D-ornithine,D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid, D-cysteine,D-penicillamine, and D-methionine;

R⁴ is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, D-valine,D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine,D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine,D-1-naphthylalanine, D-lysine, D-serine, D-ornithine,D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid, D-cysteine,D-penicillamine, D-methionine, and 2-aminothiazole-4-acetic acid;

R⁵ is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, L-valine,L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid,L-2-aminohexanoic acid, L-tyrosine, L-phenylalanine, L-thienylalanine,L-phenylglycine, L-cyclohexylalanine, L-homophenylalanine,L-1-naphthylalanine, L-lysine, L-serine, L-ornithine,L-1,2-diaminobutyric acid, L-1,2-diaminopropionic acid, L-cysteine,L-penicillamine, L-methionine, and 2-aminothiazole-4-acetic acid;

provided that one of R¹, R², R³, R⁴, and R⁵ in each Q is substitutedwith a bond to L_(n), further provided that when R² is2-aminothiazole-4-acetic acid, K is N-methylarginine, further providedthat when R⁴ is 2-aminothiazole-4-acetic acid, K and K′ areN-methylarginine, and still further provided that when R⁵ is2-aminothiazole-4-acetic acid, K′ is N-methylarginine;

d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

L_(n) is a linking group having the formula:

(CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)—(Z)_(k)—(W)_(h′)—(CR⁸R⁹)_(g″)—(W)_(h″)—(CR^(8a)R^(9a))_(g″)

 provided that g+h+g′+k+h′+g″+h″+g″′ is other than 0;

W is independently selected at each occurrence from the group: O, S, NH,NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂,(OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), (CH₂CH₂CH₂O)_(t), and(aa)_(t′);

aa is independently at each occurrence an amino acid;

Z is selected from the group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O and substituted with 0-3 R¹⁰;

R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹ and R^(9a) are independentlyselected at each occurrence from the group: H, ═O, COOH, SO₃H, PO₃H,C₁-C₅ alkyl substituted with 0-3 R¹⁰, aryl substituted with 0-3 R¹⁰,benzyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond toC_(h);

R¹⁰ is independently selected at each occurrence from the group: a bondto C_(h), COOR¹¹, OH, NHR¹¹, SO₃H, PO₃H, aryl substituted with 0-3 R¹¹,C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1R¹², and a 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-3 R¹¹;

R¹¹ is independently selected at each occurrence from the group: H, arylsubstituted with 0-1 R¹², a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹²,polyalkylene glycol substituted with 0-1 R¹², carbohydrate substitutedwith 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acidsubstituted with 0-1 R¹², polycarboxyalkyl substituted with 0-1 R¹²,polyazaalkyl substituted with 0-1 R¹², peptide substituted with 0-1 R¹²,wherein the peptide is comprised of 2-10 amino acids, and a bond toC_(h);

R¹² is a bond to C_(h);

k is selected from 0, 1, and 2;

h is selected from 0, 1, and 2;

h′ is selected from 0, 1, 2, 3, 4, and 5;

h″ is selected from 0, 1, 2, 3, 4, and 5;

g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g″′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

C_(h) is a metal bonding unit having a formula selected from the group:

A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at eachoccurrence from the group: N, NR¹³, NR¹³R¹⁴, S, SH, S(Pg), O, OH, PR¹³,PR¹³R¹⁴, P(O)R¹⁵R¹⁶, and a bond to L_(n);

E is a bond, CH, or a spacer group independently selected at eachoccurrence from the group: C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, arylsubstituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷,heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein theheterocyclo group is a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ringsystem containing 1-4 heteroatoms independently selected from N, S, andO and substituted with 0-3 R¹⁷;

R¹³, and R¹⁴ are each independently selected from the group: a bond toL_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substitutedwith 0-3 R¹⁷, C₁₋₁₀ cycloalkyl substituted with 0-3 R¹⁷,heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein theheterocyclo group is a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀aryl-substituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³or R¹⁴ is an electron, then the other is also an electron;

alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹);

R¹⁵ and R¹⁶ are each independently selected from the group: a bond toL_(n), —OH, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, C₁-C₁₀ alkylsubstituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substitutedwith 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷;

R¹⁷ is independently selected at each occurrence from the group: a bondto L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸,—C(═O)N(R¹⁸)₂, —CHO, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸,—OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂,—NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R_(18a), —SR¹⁸,—S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, NO₂,—C(═O)NHOR¹⁸, —C(═O)NHNR¹⁸R^(18a), —OCH₂CO₂H, 2-(1-morpholino)ethoxy,C₁-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylmethyl,C₂-C₆ alkoxyalkyl, aryl substituted with 0-2 R¹⁸, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O;

R¹⁸, R^(18a), and R¹⁹ are independently selected at each occurrence fromthe group: a bond to L_(n), H, C₁-C₆ alkyl, phenyl, benzyl, C₁-C₆alkoxy, halide, nitro, cyano, and trifluoromethyl;

Pg is a thiol protecting group;

R²⁰ and R²¹ are independently selected from the group: H, C₁-C₁₀ alkyl,—CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, C₂-C₁₀ 1-alkene substituted with0-3 R²³, C₂-C₁₀ 1-alkyne substituted with 0-3 R²³, aryl substituted with0-3 R²³, unsaturated 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O and substitutedwith 0-3 R²³, and unsaturated C₃₋₁₀ carbocycle substituted with 0-3 R²³;

alternatively, R²⁰ and R²¹, taken together with the divalent carbonradical to which they are attached form:

 R²² and R²³ are independently selected from the group: H, R²⁴, C₁-C₁₀alkyl substituted with 0-3 R²⁴, C₂-C₁₀ alkenyl substituted with 0-3 R²⁴,C₂-C₁₀ alkynyl substituted with 0-3 R²⁴, aryl substituted with 0-3 R²⁴,a 5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R²⁴,and C₃₋₁₀ carbocycle substituted with 0-3 R²⁴;

 alternatively, R²², R²³ taken together form a fused aromatic or a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O;

 a and b indicate the positions of optional double bonds and n is 0 or1;

R²⁴ is independently selected at each occurrence from the group: ═O, F,Cl, Br, I, —CF₃, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, —N(R²⁵)₃ ⁺,—CH₂OR²⁵, —OC(═O)R²⁵, —OC(═O)OR^(25a), —OR²⁵, —OC(═O)N(R²⁵)₂,—NR²⁶C(═O)R²⁵, —NR²⁶C(═O)OR^(25a), —NR²⁶C(═O)N(R²⁵)₂, —NR²⁶SO₂N(R²⁵)₂,—NR²⁶SO₂R^(25a), —SO₃H, —SO₂R^(25a), —SR²⁵, —S(═O)R^(25a), —SO₂N(R²⁵)₂,—N(R²⁵)₂, ═NOR²⁵, —C(═O)NHOR²⁵, —OCH₂CO₂H, and 2-(1-morpholino)ethoxy;and,

R²⁵, R^(25a), and R²⁶ are each independently selected at each occurrencefrom the group: hydrogen and C₁-C₆ alkyl;

and a pharmaceutically acceptable salt thereof.

[4] In an even more preferred embodiment, the present invention providesa compound, wherein:

L is glycine;

R¹ is an amino acid, optionally substituted with a bond to L_(n),independently selected at each occurrence from the group: L-valine,D-valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid,tyrosine, phenylalanine, phenylglycine, cyclohexylalanine,homophenylalanine, lysine, ornithine, 1,2-diaminobutyric acid, and1,2-diaminopropionic acid;

R² is an amino acid, optionally substituted with a bond to L_(n),independently selected at each occurrence from the group: valine,alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, tyrosine,L-phenylalanine, D-phenylalanine, thienylalanine, phenylglycine,biphenylglycine, cyclohexylalanine, homophenylalanine,L-1-naphthylalanine, D-1-naphthylalanine, lysine, ornithine,1,2-diaminobutyric acid, 1,2-diaminopropionic acid, and2-aminothiazole-4-acetic acid;

R³ is an amino acid, optionally substituted with a bond to L_(n),independently selected at each occurrence from the group: D-valine,D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-tyrosine, D-phenylalanine, D-phenylglycine, D-cyclohexylalanine,D-homophenylalanine, D-lysine, D-serine, D-ornithine,D-1,2-diaminobutyric acid, and D-1,2-diaminopropionic acid;

R⁴ is an amino acid, optionally substituted with a bond to L_(n),independently selected at each occurrence from the group: D-valine,D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine,D-cyclohexylalanine, D-homophenylalanine, D-1-naphthylalanine, D-lysine,D-ornithine, D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid, and2-aminothiazole-4-acetic acid;

R⁵ is an amino acid, optionally substituted with a bond to L_(n),independently selected at each occurrence from the group: L-valine,L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid,L-tyrosine, L-phenylalanine, L-thienylalanine, L-phenylglycine,L-cyclohexylalanine, L-homophenylalanine, L-1-naphthylalanine, L-lysine,L-ornithine, L-1,2-diaminobutyric acid, L-1,2-diaminopropionic acid, and2-aminothiazole-4-acetic acid;

d is selected from 1, 2, and 3;

W is independently selected at each occurrence from the group: O, NH,NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂,(OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), and (CH₂CH₂CH₂O)_(t),

Z is selected from the group: aryl substituted with 0-1 R¹⁰, C₃₋₁₀cycloalkyl substituted with 0-1 R¹⁰, and a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O and substituted with 0-1 R¹⁰;

R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹, and R^(9a) are independentlyselected at each occurrence from the group: H, ═O, COOH, SO₃H, C₁-C₅alkyl substituted with 0-1 R¹⁰, aryl substituted with 0-1 R¹⁰, benzylsubstituted with 0-1 R¹⁰, and C₁-C₅ alkoxy substituted with 0-1 R¹⁰,NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to C_(h);

R¹⁰ is independently selected at each occurrence from the group: COOR¹¹,OH, NHR¹¹, SO₃H, aryl substituted with 0-1 R¹¹, a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-1 R¹¹, C₁-C₅ alkylsubstituted with 0-1 R¹², C₁-C₅ alkoxy substituted with 0-1 R¹², and abond to C_(h);

R¹¹ is independently selected at each occurrence from the group: H, arylsubstituted with 0-1 R¹², a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-1 R¹², polyalkylene glycol substituted with 0-1 R¹²,carbohydrate substituted with 0-1 R¹², cyclodextrin substituted with 0-1R¹², amino acid substituted with 0-1 R¹², and a bond to C_(h);

k is 0 or 1;

h is 0 or 1;

h′ is 0 or 1;

s is selected from 0, 1, 2, 3, 4, and 5;

s′ is selected from 0, 1, 2, 3, 4, and 5;

s″ is selected from 0, 1, 2, 3, 4, and 5;

t is selected from 0, 1, 2, 3, 4, and 5;

A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at eachoccurrence from the group: NR¹³, NR¹³R¹⁴, S, SH, S(Pg), OH, and a bondto L_(n);

E is a bond, CH, or a spacer group independently selected at eachoccurrence from the group: C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, arylsubstituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, anda 5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷;

R¹³, and R¹⁴ are each independently selected from the group: a bond toL_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substitutedwith 0-3 R¹⁷, a 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-3 R¹⁷, and an electron, provided that when one of R¹³ or R¹⁴ is anelectron, then the other is also an electron;

alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹);

R¹⁷ is independently selected at each occurrence from the group: a bondto L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸,—C(═O)N(R¹⁸)₂, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸,—OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂,—NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —S(═O)R^(18a),—SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, —C(═O)NHNR¹⁸R^(18a),—OCH₂CO₂H, and 2-(1-morpholino)ethoxy;

R¹⁸, R^(18a), and R¹⁹ are independently selected at each occurrence fromthe group: a bond to L_(n), H, and C₁-C₆ alkyl;

R²⁰ and R²¹ are independently selected from the group: H, C₁-C₅ alkyl,—CO₂R²⁵, C₂-C₅ 1-alkene substituted with 0-3 R²³, C₂-C₅ 1-alkynesubstituted with 0-3 R²³, aryl substituted with 0-3 R²³, and unsaturated5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R²³;

alternatively, R²⁰ and R²¹, taken together with the divalent carbonradical to which they are attached form:

R²² and R²³ are independently selected from the group: H, and R²⁴;

alternatively, R²², R²³ taken together form a fused aromatic or a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O;

R²⁴ is independently selected at each occurrence from the group:—CO₂R²⁵, —C(═O)N(R²⁵)₂, —CH₂OR²⁵, —OC(═O)R²⁵, —OR²⁵, —SO₃H, —N(R²⁵)₂,and —OCH₂CO₂H; and,

R²⁵ is independently selected at each occurrence from the group: H andC₁-C₃ alkyl.

[5] In a still more preferred embodiment, the present invention providesa compound, wherein:

Q is a peptide selected from the group:

R¹ is L-valine, D-valine, D-lysine optionally substituted on the ε aminogroup with a bond to L_(n) or L-lysine optionally substituted on the εamino group with a bond to L_(n);

R² is L-phenylalanine, D-phenylalanine, D-1-naphthylalanine,2-aminothiazole-4-acetic acid, L-lysine optionally substituted on the εamino group with a bond to L_(n) or tyrosine, the tyrosine optionallysubstituted on the hydroxy group with a bond to L_(n);

R³ is D-valine, D-phenylalanine, or L-lysine optionally substituted onthe ε amino group with a bond to L_(n);

R⁴ is D-phenylalanine, D-tyrosine substituted on the hydroxy group witha bond to L_(n), or L-lysine optionally substituted on the ε amino groupwith a bond to L_(n);

provided that one of R¹ and R² in each Q is substituted with a bond toL_(n), and further provided that when R² is 2-aminothiazole-4-aceticacid, K is N-methylarginine;

d is 1 or 2;

W is independently selected at each occurrence from the group: NHC(═O),C(═O)NH, C(═O), (CH₂CH₂O)_(s′), and (CH₂CH₂CH₂O)_(t);

R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹, and R^(9a) are independentlyselected at each occurrence from the group: H, NHC(═O)R¹¹, and a bond toC_(h);

k is 0;

h″ is selected from 0, 1, 2, and 3;

g is selected from 0, 1, 2, 3, 4, and 5;

g′ is selected from 0, 1, 2, 3, 4, and 5;

g″ is selected from 0, 1, 2, 3, 4, and 5;

g″′ is selected from 0, 1, 2, 3, 4, and 5;

s′ is 1 or 2;

t is 1 or 2;

C_(h) is

A¹ is selected from the group: OH, and a bond to L_(n);

A², A⁴, and A⁶ are each N;

A³, A⁵, and A⁸ are each OH;

A⁷ is a bond to L_(n) or NH-bond to L_(n);

E is a C₂ alkyl substituted with 0-1 R¹⁷;

R¹⁷ is ═O;

alternatively, C_(h) is

A¹ is NH₂ or N═C(R²⁰)(R²¹);

E is a bond;

A² is NHR¹³;

R¹³ is a heterocycle substituted with R¹⁷, the heterocycle beingselected from pyridine and pyrimidine;

R¹⁷ is selected from a bond to L_(n), C(═O)NHR¹⁸, and C(═O)R¹⁸;

R¹⁸ is a bond to L_(n);

 R²⁴ is selected from the group: —CO₂R²⁵, —OR²⁵, —SO₃H, and —N(R²⁵)₂;

 R²⁵ is independently selected at each occurrence from the group:hydrogen and methyl;

alternatively, C_(h) is

A¹, A², A³, and A⁴ are each N;

A⁵, A⁶, and A⁸ are each OH;

A⁷ is a bond to L_(n);

E is a C₂ alkyl substituted with 0-1 R¹⁷; and,

R¹⁷ is ═O.

[6] In another even more preferred embodiment, the present inventionprovides a compound selected from the group:

(a)cyclo{Arg-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val};

(b)cyclo{Arg-Gly-Asp-D-Tyr((N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-18-amino-14-aza-4,7,10-oxy-15-oxo-octadecoyl)-3-aminopropyl)-Val};

(c) [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Tyr(3-aminopropyl)-Val-Agr-Gly-Asp})-cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp);

(d)cyclo(Arg-Gly-Asp-D-Tyr-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])};

(e)cyclo{Arg-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])};

(f) [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe);

(g) [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Phe-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};

(h)cyclo{Arg-Gly-Asp-D-Nal-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])};

(i) [2-[[[5-[carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal);

(j)cyclo{Arg-Gly-Asp-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Val};

(k) [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-D-Val-Arg-Gly-Asp})-cyclo{Lys-D-Val-Arg-Gly-Asp};

(l){cyclo(Arg-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly};

(m)cyclo{D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Phe-D-Asp-Gly-Arg};

(n) [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg};

(o)cyclo{D-Phe-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Asp-Gly-Arg};

(p)cyclo{N-Me-Arg-Gly-Asp-ATA-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])};

(q)cyclo{Cit-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])};

(r)2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};

(s) cyclo{Arg-Gly-Asp-D-Phe-Lys(DTPA)};

(t) cyclo{Arg-Gly-Asp-D-Phe-Lys}₂(DTPA);

(u) Cyclo{Arg-Gly-Asp-D-Tyr(N-DTPA-3-aminopropyl)-Val};

(v)cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val};

(w)cyclo{Lys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val};

(x)cyclo{Cys(2-aminoethyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val};

(y)cyclo{HomoLys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val};

(z)cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val};

(aa)cyclo{Dap(b-(2-benzimidazolylacetyl))-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val};

(bb)cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])};

(cc)cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])};

(dd)cyclo{Lys-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly};

(ee)cyclo{Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; and,

(ff)cyclo{Orn(d-N-2-Imidazolinyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly};

or a pharmaceutically acceptable salt form thereof.

[7] In a further preferred embodiment, the present invention provides akit comprising a compound of the present invention.

[8] In an even further preferred embodiment, the kit further comprisesone or more ancillary ligands and a reducing agent.

[9] In a still further preferred embodiment, the ancillary ligands aretricine and TPPTS.

[10] In another still further preferred embodiment, the reducing agentis tin(II).

[11] In a second embodiment, the present invention provides a noveldiagnostic or therapeutic metallopharmaceutical compostion, comprising:a metal, a chelator capable of chelating the metal and a targetingmoiety, wherein the targeting moiety is bound to the chelator, is apeptide or peptidomimetic and binds to a receptor that is upregulatedduring angiogenesis and the compound has 0-1 linking groups between thetargeting moiety and chelator.

[12] In another preferred embodiment, the metallopharmaceutical is adiagnostic radiopharmaceutical, the metal is a radioisotope selectedfrom the group: ^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, and ⁶⁸Ga, thetargeting moiety is a peptide or a mimetic thereof and the receptor isselected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie,neuropilin-1, endoglin, endosialin, Axl, α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁,α₁β₁, and α₂β₂ and the linking group is present between the targetingmoiety and chelator.

[13] In another more preferred embodiment, the targeting moiety is acyclic pentapeptide and the receptor is α_(v)β₃.

[14] In another even more preferred embodiment, the radioisotope is^(99m)Tc or ⁹⁵Tc, the radiopharmaceutical further comprises a firstancillary ligand and a second ancillary ligand capable of stabilizingthe radiopharmaceutical.

[15] In another still more preferred embodiment, the radioisotope is^(99m)Tc.

[16] In another further preferred embodiment, the radiopharmaceutical isselected from the group:

^(99m)Tc(tricine)(TPPTS)(cyclo(Arg-Gly-Asp-D-Tyr(N-[[5-[carbonyl]-2-pyridinyl]diazenido]-3-aminopropyl)-Val));

^(99m)Tc(tricine)(TPPMS)(cyclo(Arg-D-Val-D-Tyr(N-[[5-[carbonyl]-2-pyridinyl]diazenido]-3-aminopropyl)-D-Asp-Gly));

^(99m)Tc(tricine)(TPPDS)(cyclo(Arg-D-Val-D-Tyr(N-[[5-[carbonyl]-2-pyridinyl]diazenido]-3-aminopropyl)-D-Asp-Gly));

^(99m)Tc(tricine)(TPPTS)(cyclo(Arg-D-Val-D-Tyr(N-[[5-[carbonyl]-2-pyridinyl]diazenido]-3-aminopropyl)-D-Asp-Gly));

^(99m)Tc(tricine)(TPPTS)(cyclo(Arg-Gly-Asp-D-Phe-Lys(N-[[5-[carbonyl]-2-pyridinyl]diazenido])));

^(99m)Tc(tricine)(TPPTS)(cyclo(Arg-Gly-Asp-D-Tyr-Lys(N-[[5-[carbonyl]-2-pyridinyl]diazenido])));

^(99m)Tc(tricine)(TPPTS)([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Phe-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe});

^(99m)Tc(tricine)(TPPTS)(cyclo{Arg-Gly-Asp-D-Nal-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])});

^(99m)Tc(tricine)(TPPTS)([2-[[[5-[carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal});

^(99m)Tc(tricine)(TPPTS)(cyclo(Arg-Gly-Asp-D-Tyr((N-[[5-[carbonyl]-2-pyridinyl]diazenido]-18-amino-14-aza-4,7,10-oxy-15-oxo-octadecoyl)-3-aminopropyl)-Val));

^(99m)Tc(tricine)(TPPTS)(N-[[5-[carbonyl]-2-pyridinyl]diazenido]-Glu(O-cyclo(Lys-Arg-Gly-Asp-D-Phe))-O-cyclo(Lys-Arg-Gly-Asp-D-Phe));

^(99m)Tc(tricine)(TPPTS)(N-[[5-[carbonyl]-2-pyridinyl]diazenido]-Glu(O-cyclo(D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp))-O-cyclo(D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp));

^(99m)Tc(tricine)(TPPTS)(cyclo(Arg-Gly-Asp-Lys(N-[[5-[carbonyl]-2-pyridinyl]diazenido])-D-Val));

^(99m)Tc(tricine)(TPPTS)(cyclo{D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Phe-D-Asp-Gly-Arg});

^(99m)Tc(tricine)(TPPTS)([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg});

^(99m)Tc(tricine)(TPPTS)(cyclo{D-Phe-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Asp-Gly-Arg});

^(99m)Tc(tricine)(TPPTS)(cyclo(N-Me-Arg-Gly-Asp-ATA-D-Lys(N-[[5-[carbonyl]-2-pyridinyl]diazenido])));

^(99m)Tc(tricine)(TPPTS)(cyclo{Cit-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}); and,

^(99m)Tc(tricine)(1,2,4-triazole)(cyclo(Arg-Gly-Asp-D-Tyr(N-[[5-[carbonyl]-2-pyridinyl]diazenido]-3-aminopropyl)-Val)).

[17] In another even more preferred embodiment, the radioisotope is¹¹¹In.

[18] In another still more preferred embodiment, the radiopharmaceuticalis selected from the group:

(DOTA-¹¹¹In)-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};

cyclo(Arg-Gly-Asp-D-Phe-Lys(DTPA-¹¹¹In)); and,

cyclo(Arg-Gly-Asp-D-Phe-Lys)₂ (DTPA-¹¹¹In).

[19] In another preferred embodiment, the metallopharmaceutical is atherapeutic radiopharmaceutical, the metal is a radioisotope selectedfrom the group: ³³P, ¹²⁵I, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm,⁹⁰Y, ²¹²Bi, ¹⁰³Pd, ¹⁰⁹Pd, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁶⁹Yb, ¹⁷⁵Yb,¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, ¹⁰⁵Rh, ¹¹¹Ag, and ¹⁹²Ir, the targeting moiety is apeptide or a mimetic thereof and the receptor is selected from thegroup: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1,endoglin, endosialin, Axl, α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁, α₁β₁, and α₂β₂and the linking group is present between the targeting moiety andchelator.

[20] In another more preferred embodiment, the targeting moiety is acyclic pentapeptide and the receptor is α_(v)β₃.

[21] In another even more preferred embodiment, the radioisotope is¹⁵³Sm.

[22] In another still more preferred embodiment, the radiopharmaceuticalis selected from the group:

cyclo(Arg-Gly-Asp-D-Phe-Lys(DTPA-¹⁵³Sm));

cyclo(Arg-Gly-Asp-D-Phe-Lys)₂(DTPA-¹⁵³Sm); and,

cyclo(Arg-Gly-Asp-D-Tyr(N-DTPA(¹⁵³Sm)-3-aminopropyl)-Val).

[23] In another even more preferred embodiment, the radioisotope is¹⁷⁷Lu.

[24] In another still more preferred embodiment, the radiopharmaceuticalis selected from the group:

cyclo(Arg-Gly-Asp-D-Phe-Lys(DTPA-¹⁷⁷Lu));

(DOTA-¹⁷⁷Lu)-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo}Lys-Arg-Gly-Asp-D-Phe};

cyclo(Arg-Gly-Asp-D-Phe-Lys)₂(DTPA-¹⁷⁷Lu); and,

cyclo(Arg-Gly-Asp-D-Tyr(N-DTPA(¹⁷⁷Lu)-3-aminopropyl)-Val).

[25] In another even more preferred embodiment, the radioisotope is ⁹⁰Y.

[26] In another still more preferred embodiment, the radiopharmaceuticalis:

(DOTA-⁹⁰Y)-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};

[27] In another preferred embodiment, the metallopharmaceutical is a MRIcontrast agent, the metal is a paramagnetic metal ion selected from thegroup: Gd(III), Dy(III), Fe(III), and Mn(II), the targeting moiety is apeptide or a mimetic thereof and the receptor is selected from thegroup: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1,endoglin, endosialin, Axl, α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁, α₁β₁, and α₂β₂and the linking group is present between the targeting moiety andchelator.

[28] In another more preferred embodiment, the targeting moiety is acyclic pentapeptide and the receptor is α_(v)β₃.

[29] In another even more preferred embodiment, the metal ion isGd(III).

[30] In another still more preferred embodiment, the contrast agent is:

cyclo(Arg-Gly-Asp-D-Tyr(N-DTPA(Gd(III))-3-aminopropyl)-Val).

[31] In another preferred embodiment, the metallopharmaceutical is aX-ray contrast agent, the metal is selected from the group: Re, Sm, Ho,Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir, thetargeting moiety is a cyclic pentapeptide, the receptor is α_(v)β₃, andthe linking group is present between the targeting moiety and chelator.

[32] In another even more preferred embodiment, the present inventionprovides a novel method of treating rheumatoid arthritis in a patientcomprising: administering a therapeutic radiopharmaceutical of thepresent invention capable of localizing in new angiogenic vasculature toa patient by injection or infusion.

[33] In another even more preferred embodiment, the present inventionprovides a novel method of treating cancer in a patient comprising:administering to a patient in need thereof a therapeuticradiopharmaceutical of the present invention by injection or infusion.

[34] In another even more preferred embodiment, the present inventionprovides a novel method of imaging formation of new blood vessels in apatient comprising: (1) administering a diagnostic radiopharmaceutical,a MRI contrast agent, or a X-ray contrast agent of the present inventionto a patient by injection or infusion; (2) imaging the area of thepatient wherein the desired formation of new blood vessels is located.

[35] In another even more preferred embodiment, the present inventionprovides a novel method of imaging cancer in a patient comprising: (1)administering a diagnostic radiopharmaceutical of the present inventionto a patient by injection or infusion; (2) imaging the patient usingplanar or SPECT gamma scintigraphy, or positron emission tomography.

[36] In another even more preferred embodiment, the present inventionprovides a novel method of imaging cancer in a patient comprising: (1)administering a MRI contrast agent of the present invention; and (2)imaging the patient using magnetic resonance imaging.

[37] In another even more preferred embodiment, the present inventionprovides a novel method of imaging cancer in a patient comprising: (1)administering a X-ray contrast agent of the present invention; and (2)imaging the patient using X-ray computed tomography.

[38] In a third embodiment, the present invention provides a novelcompound capable of being used in an ultrasound contrast composition,comprising: a targeting moiety and a surfactant, wherein the targetingmoiety is bound to the surfactant, is a peptide or peptidomimetic, andbinds to a receptor that is upregulated during angiogenesis and thecompound has 0-1 linking groups between the targeting moiety andsurfactant.

[39] In a preferred embodiment, the targeting moiety is a peptide or amimetic thereof and the receptor is selected from the group: EGFR, FGFR,PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin,Axl, α_(v)β₃, α_(v)β₅α₅β₁, α₄β₁, α₁β₁, and α₂β₂ and the linking group ispresent between the targeting moiety and surfactant.

[40] In a more preferred embodiment, the receptor is the integrinα_(v)β₃ and the compound is of the formula:

(Q)_(d)—L_(n)—S_(f)

wherein, Q is a cyclic pentapeptide independently selected from thegroup:

K is an L-amino acid independently selected at each occurrence from thegroup: arginine, citrulline, N-methylarginine, lysine, homolysine,2-aminoethylcysteine, δ-N-2-imidazolinylornithine,δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid;

K′ is a D-amino acid independently selected at each occurrence from thegroup: arginine, citrulline, N-methylarginine, lysine, homolysine,2-aminoethylcysteine, δ-N-2-imidazolinylornithine,δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid;

L is independently selected at each occurrence from the group: glycine,L-alanine, and D-alanine;

M is L-aspartic acid;

M′ is D-aspartic acid;

R¹ is an amino acid substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, L-valine, D-valine,alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid,2-aminohexanoic acid, tyrosine, phenylalanine, thienylalanine,phenylglycine, cyclohexylalanine, homophenylalanine, 1-naphthylalanine,lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionicacid, cysteine, penicillamine, and methionine;

R² is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, valine, alanine,leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoicacid, tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine,phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine,L-1-naphthylalanine, D-1-naphthylalanine, lysine, serine, ornithine,1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine,penicillamine, methionine, and 2-aminothiazole-4-acetic acid;

R³ is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, D-valine,D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine,D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine,D-1-naphthylalanine, D-lysine, D-serine, D-ornithine,D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid, D-cysteine,D-penicillamine, and D-methionine;

R⁴ is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, D-valine,D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine,D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine,D-1-naphthylalanine, D-lysine, D-serine, D-ornithine,D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid, D-cysteine,D-penicillamine, D-methionine, and 2-aminothiazole-4-acetic acid;

R⁵ is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, L-valine,L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid,L-2-aminohexanoic acid, L-tyrosine, L-phenylalanine, L-thienylalanine,L-phenylglycine, L-cyclohexylalanine, L-homophenylalanine,L-1-naphthylalanine, L-lysine, L-serine, L-ornithine,L-1,2-diaminobutyric acid, L-1,2-diaminopropionic acid, L-cysteine,L-penicillamine, L-methionine, and 2-aminothiazole-4-acetic acid;

provided that one of R¹, R², R³, R⁴, and R⁵ in each Q is substitutedwith a bond to L_(n), further provided that when R² is2-aminothiazole-4-acetic acid, K is N-methylarginine, further providedthat when R⁴ is 2-aminothiazole-4-acetic acid, K and K′ areN-methylarginine, and still further provided that when R⁵ is2-aminothiazole-4-acetic acid, K′ is N-methylarginine;

d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

S_(f) is a surfactant which is a lipid or a compound of the formula:

A⁹ is selected from the group: OH and OR²⁷;

A¹⁰ is OR²⁷;

R²⁷ is C(═O)C₁₋₂₀ alkyl;

E¹ is C₁₋₁₀ alkylene substituted with 1-3 R²⁸;

R²⁸ is independently selected at each occurrence from the group: R³⁰,—PO₃H—R³⁰, ═O, —CO₂R²⁹, —C(═O)R²⁹, —C(═O)N(R²⁹)₂, —CH₂OR²⁹, —OR²⁹,—N(R²⁹)₂, C₁-C₅ alkyl, and C₂-C₄ alkenyl;

R²⁹ is independently selected at each occurrence from the group: R³⁰, H,C₁-C₆ alkyl, phenyl, benzyl, and trifluoromethyl;

R³⁰ is a bond to L_(n);

L_(n) is a linking group having the formula:

(CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)—(Z)_(k)—(W)_(h′)—(CR⁸R⁹)_(g″)—(W)_(h″)—(CR^(8a)R^(9a))_(g″)

W is independently selected at each occurrence from the group: O, S, NH,NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂,(OCH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂O)₂₀₋₂₀₀, (OCH₂CH₂CH₂)₂₀₋₂₀₀,(CH₂CH₂CH₂O)₂₀₋₂₀₀, and (aa)_(t′);

aa is independently at each occurrence an amino acid;

z is selected from the group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O and substituted with 0-3 R¹⁰;

R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹ and R^(9a) are independentlyselected at each occurrence from the group: H, ═O, COOH, SO₃H, PO₃H,C₁-C₅ alkyl substituted with 0-3 R¹⁰, aryl substituted with 0-3 R¹⁰,benzyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond toS_(f);

R¹⁰ is independently selected at each occurrence from the group: a bondto S_(f), COOR¹¹, OH, NHR¹¹, SO₃H, PO₃H, aryl substituted with 0-3 R¹¹,C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1R¹², and a 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-3 R¹¹;

R¹¹ is independently selected at each occurrence from the group: H, arylsubstituted with 0-1 R¹², a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹²,amino acid substituted with 0-1 R¹², and a bond to S_(f);

R¹² is a bond to S_(f);

k is selected from 0, 1, and 2;

h is selected from 0, 1, and 2;

h′ is selected from 0, 1, 2, 3, 4, and 5;

h″ is selected from 0, 1, 2, 3, 4, and 5;

g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g″′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

and a pharmaceutically acceptable salt thereof.

[41] In another even more preferred embodiment, the compound is of theformula:

 Q—L_(n)—S_(f)

wherein, Q is a cyclic pentapeptide independently selected from thegroup:

K is an L-amino acid independently selected at each occurrence from thegroup: arginine, citrulline, N-methylarginine, lysine, homolysine,2-aminoethylcysteine, δ-N-2-imidazolinylornithine,δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid;

K′ is a D-amino acid independently selected at each occurrence from thegroup: arginine, citrulline, N-methylarginine, lysine, homolysine,2-aminoethylcysteine, δ-N-2-imidazolinylornithine,δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid;

L is independently selected at each occurrence from the group: glycine,L-alanine, and D-alanine;

M is L-aspartic acid;

M′ is D-aspartic acid;

R¹ is an amino acid substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, L-valine, D-valine,alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid,2-aminohexanoic acid, tyrosine, phenylalanine, thienylalanine,phenylglycine, cyclohexylalanine, homophenylalanine, 1-naphthylalanine,lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionicacid, cysteine, penicillamine, and methionine;

R² is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, valine, alanine,leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoicacid, tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine,phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine,L-1-naphthylalanine, D-1-naphthylalanine, lysine, serine, ornithine,1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine,penicillamine, methionine, and 2-aminothiazole-4-acetic acid;

R³ is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, D-valine,D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine,D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine,D-1-naphthylalanine, D-lysine, D-serine, D-ornithine,D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid, D-cysteine,D-penicillamine, and D-methionine;

R⁴ is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, D-valine,D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine,D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine,D-1-naphthylalanine, D-lysine, D-serine, D-ornithine,D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid, D-cysteine,D-penicillamine, D-methionine, and 2-aminothiazole-4-acetic acid;

R⁵ is an amino acid, substituted with 0-1 bonds to L_(n), independentlyselected at each occurrence from the group: glycine, L-valine,L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid,L-2-aminohexanoic acid, L-tyrosine, L-phenylalanine, L-thienylalanine,L-phenylglycine, L-cyclohexylalanine, L-homophenylalanine,L-1-naphthylalanine, L-lysine, L-serine, L-ornithine,L-1,2-diaminobutyric acid, L-1,2-diaminopropionic acid, L-cysteine,L-penicillamine, L-methionine, and 2-aminothiazole-4-acetic acid;

provided that one of R¹, R², R³, R⁴, and R⁵ in each Q is substitutedwith a bond to L_(n), further provided that when R² is2-aminothiazole-4-acetic acid, K is N-methylarginine, further providedthat when R⁴ is 2-aminothiazole-4-acetic acid, K and K′ areN-methylarginine, and still further provided that when R⁵ is2-aminothiazole-4-acetic acid, K′ is N-methylarginine;

S_(f) is a surfactant which is a lipid or a compound of the formula:

A⁹ is OR²⁷;

A¹⁰ is OR²⁷;

R²⁷ is C(═O)C₁₋₁₅ alkyl;

E¹ is C₁₋₄ alkylene substituted with 1-3 R²⁸;

R²⁸ is independently selected at each occurrence from the group: R³⁰,—PO₃H—R³⁰, ═O, —CO₂R²⁹, —C(═O)R²⁹, —CH₂OR²⁹, —OR²⁹, and C₁-C₅ alkyl;

R²⁹ is independently selected at each occurrence from the group: R³⁰, H,C₁-C₆ alkyl, phenyl, and benzyl;

R³⁰ is a bond to L_(n);

L_(n) is a linking group having the formula:

(CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)—(Z)_(k)—(W)_(h′)—(CR⁸R⁹)_(g″)—(W)_(h″)—(CR^(8a)R^(9a))_(g″)

W is independently selected at each occurrence from the group: O, S, NH,NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂,(OCH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂O)₂₀₋₂₀₀, (OCH₂CH₂CH₂)₂₀₋₂₀₀,(CH₂CH₂CH₂O)₂₀₋₂₀₀, and (aa)_(t′);

aa is independently at each occurrence an amino acid;

Z is selected from the group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O and substituted with 0-3 R¹⁰;

R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹ and R^(9a) are independentlyselected at each occurrence from the group: H, ═O, C₁-C₅ alkylsubstituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3 R¹⁰, anda bond to S_(f);

R¹⁰ is independently selected at each occurrence from the group: a bondto S_(f), COOR¹¹, OH, NHR¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², andC₁₋₅ alkoxy substituted with 0-1 R¹²;

R¹¹ is independently selected at each occurrence from the group: H, arylsubstituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹²,amino acid substituted with 0-1 R¹², and a bond to S_(f);

 R¹² is a bond to S_(f);

 k is selected from 0, 1, and 2;

 h is selected from 0, 1, and 2;

 h′ is selected from 0, 1, 2, 3, 4, and 5;

 h″ is selected from 0, 1, 2, 3, 4, and 5;

 g is selected from 0, 1, 2, 3, 4, and 5;

 g′ is selected from 0, 1, 2, 3, 4, and 5;

 g″ is selected from 0, 1, 2, 3, 4, and 5;

 g″′ is selected from 0, 1, 2, 3, 4, and 5;

 s is selected from 0, 1, 2, 3, 4, and 5;

 s′ is selected from 0, 1, 2, 3, 4, and 5;

 s″ is selected from 0, 1, 2, 3, 4, and 5;

 t is selected from 0, 1, 2, 3, 4, and 5;

 t′ is selected from 0, 1, 2, 3, 4, and 5;

and a pharmaceutically acceptable salt thereof.

[42] In another still more preferred embodiment, the present inventionprovides a compound selected from the group:

1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-(cyclo(Arg-Gly-Asp-D-Phe-Lys)-dodecane-1,12-dione;

1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-((ω-amino-PEG₃₄₀₀-α-carbonyl)-cyclo(Arg-Gly-Asp-D-Phe-Lys))-dodecane-1,12-dione;and,

1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-((ω-amino-PEG₃₄₀₀-α-carbonyl)-Glu-(cyclo(Arg-Gly-Asp-D-Phe-Lys))₂)-Dodecane-1,12-dione.

[43] In another even more preferred embodiment, the present inventionprovides a novel ultrasound contrast agent composition, comprising:

(a) a compound comprising: a cyclic pentapeptide that binds to theintegrin α_(v)β₃, a surfactant and a linking group between thecyclicpentapeptide and the surfactant;

(b) a parenterally acceptable carrier; and,

(c) an echogenic gas.

[44] In another still more preferred embodiment, the ultrasound contrastagent further comprises: 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid,1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, andN-(methoxypolyethylene glycol 5000carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine.

[45] In another further preferred embodiment, the echogenic gas is aC₂₋₅ perfluorocarbon.

[46] In another even more preferred embodiment, the present inventionprovides a method of imaging cancer in a patient comprising: (1)administering, by injection or infusion, a ultrasound contrast agentcomposition of the present invention to a patient; and (2) imaging thepatient using sonography.

[47] In another even more preferred embodiment, the present inventionprovides a novel method of imaging formation of new blood vessels in apatient comprising: (1) administering, by injection or infusion, aultrasound contrast agent composition of the present invention to apatient; (2) imaging the area of the patient wherein the desiredformation of new blood vessels is located.

[48] In another even more preferred embodiment, the present inventionprovides a novel therapeutic radiopharmaceutical composition,comprising:

(a) a therapeutic radiopharmaceutical of the present invention; and,

(b) a parenterally acceptable carrier.

[49] In another even more preferred embodiment, the present inventionprovides a novel diagnostic radiopharmaceutical composition, comprising:

(a) a diagnostic radiopharmaceutical, a MRI contrast agent, or a X-raycontrast agent of the present invention; and,

(b) a parenterally acceptable carrier.

[50] In another even more preferred embodiment, the present inventionprovides a novel therapeutic radiopharmaceutical composition,comprising: a radiolabelled targeting moiety, wherein the targetingmoiety is a compound Q and the radiolabel is a therapeutic isotopeselected from the group: ³⁵S, ³²P, ¹²⁵I, ¹³¹I, and ²¹¹At.

[51] In another further preferred embodiment, the present inventionprovides a novel therapeutic radiopharmaceutical composition,comprising: a radiolabelled targeting moiety, wherein the targetingmoiety is a compound Q and the radiolabel is a therapeutic isotope whichis ¹³¹I.

[52] In another preferred embodiment, the present invention provides akit for treating cancer, comprising a compound of Embodiment 1, or apharmaceutically acceptable salt thereof, and at least one agentselected from the group consisting of a chemotherapeutic agent and aradiosensitizer agent, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

[53] In another preferred embodiment, the present invention provides akit according to Embodiment 52 wherein said kit comprises a plurality ofseparate containers, wherein at least one of said containers contains acompound of Embodiment 1, or a pharmaceutically acceptable salt thereof,and at least another of said containers contains one or more agentsselected from the group consisting of a chemotherapeutic agent and aradiosensitizer agent, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

[54] In another preferred embodiment, the present invention provides akit according to Embodiment 52, wherein the chemotherapeutic agent isselected from the group consisting of mitomycin, tretinoin, ribomustin,gemcitabine, vincristine, etoposide, cladribine, mitobronitol,methotrexate, doxorubicin, carboquone, pentostatin, nitracrine,zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole,fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine,bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine,proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate,isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil,butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol,tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide,improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen,progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha,interferon-2 alpha, interferon-beta, interferon-gamma, colonystimulating factor-1, colony stimulating factor-2, denileukin diftitox,interleukin-2, and leutinizing hormone releasing factor.

[55] In another preferred embodiment, the present invention provides akit according to Embodiment 52, wherein the chemotherapeutic agent isselected from the group consisting of mitomycin, tretinoin, ribomustin,gemcitabine, vincristine, etoposide, cladribine, mitobronitol,methotrexate, doxorubicin, carboquone, pentostatin, nitracrine,zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole,fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine,bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine,proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate,isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil,butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol,tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide,improsulfan, enocitabine, and lisuride.

[56] In another preferred embodiment, the present invention provides akit according to Embodiment 52 wherein the chemotherapeutic agent isselected from the group consisting of oxymetholone, tamoxifen,progesterone, mepitiostane, epitiostanol, and formestane.

[57] In another preferred embodiment, the present invention provides akit according to Embodiment 52 wherein the chemotherapeutic agent isselected from the group consisting of interferon-alpha, interferon-2alpha, interferon-beta, interferon-gamma, colony stimulating factor-1,colony stimulating factor-2, denileukin diftitox, interleukin-2, andleutinizing hormone releasing factor.

[58] In another preferred embodiment, the present invention provides akit according to Embodiment 52, wherein radiosensitizer agent isselected from the group consiting of2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide,N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine,3-amino-1,2,4-benzotriazine-1,4-dioxide,N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide,1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol.

[59] In another preferred embodiment, the present invention provides atherapeutic metallopharmaceutical composition according to Embodiment11, wherein the metallopharmaceutical is a therapeuticradiopharmaceutical, further comprising at least one agent selected fromthe group consisting of a chemotherapeutic agent and a radiosensitizeragent, or a pharmaceutically acceptable salt thereof.

[60] In another preferred embodiment, the present invention provides atherapeutic metallopharmaceutical composition according to Embodiment59, wherein the chemotherapeutic agent is selected from the groupconsisting of mitomycin, tretinoin, ribomustin, gemcitabine,vincristine, etoposide, cladribine, mitobronitol, methotrexate,doxorubicin, carboquone, pentostatin, nitracrine, zinostatin,cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole,fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine,bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine,proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate,isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil,butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol,tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide,improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen,progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha,interferon-2 alpha, interferon-beta, interferon-gamma, colonystimulating factor-1, colony stimulating factor-2, denileukin diftitox,interleukin-2, and leutinizing hormone releasing factor.

[61] In another preferred embodiment, the present invention provides atherapeutic metallopharmaceutical composition according to Embodiment59, wherein radiosensitizer agent is selected from the group consitingof 2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide,N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine,3-amino-1,2,4-benzotriazine-1,4-dioxide,N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide,1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol.

[62] In another preferred embodiment, the present invention provides amethod of treating cancer in a patient comprising: administering to apatient in need thereof a therapeutic radiopharmaceutical of Embodiment19 or a pharmaceutically acceptable salt thereof, and at least one agentselected from the group consisting of a chemotherapeutic agent and aradiosensitizer agent, or a pharmaceutically acceptable salt thereof.

[63] In another preferred embodiment, the present invention provides amethod of treating cancer according to Embodiment 62, wherein theadministration is by injection or infusion.

[64] In another preferred embodiment, the present invention provides amethod according to Embodiment 62 wherein administering the therapeuticradiopharmaceutical and agent is concurrent.

[65] In another preferred embodiment, the present invention provides amethod according to Embodiment 62 wherein administering the therapeuticradiopharmaceutical and agent is sequential.

[66] In another preferred embodiment, the present invention provides amethod according to Embodiment 62 wherein the cancer is selected fromthe group consisting of carcinomas of the lung, breast, ovary, stomach,pancreas, larynx, esophagus, testes, liver, parotid, biliary tract,colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate,thyroid, squamous cell carcinomas, adenocarcinomas, small cellcarcinomas, melanomas, gliomas, and neuroblastomas.

[67] In another preferred embodiment, the present invention provides amethod according to Embodiment 62 wherein the chemotherapeutic agent isselected from the group consisting of mitomycin, tretinoin, ribomustin,gemcitabine, vincristine, etoposide, cladribine, mitobronitol,methotrexate, doxorubicin, carboquone, pentostatin, nitracrine,zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole,fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine,bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine,proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate,isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil,butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol,tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide,improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen,progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha,interferon-2 alpha, interferon-beta, interferon-gamma, colonystimulating factor-1, colony stimulating factor-2, denileukin diftitox,interleukin-2, and leutinizing hormone releasing factor.

[68] In another preferred embodiment, the present invention provides amethod according to Embodiment 62 wherein the radiosensitizer agent isselected from the group consiting of2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide,N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine,3-amino-1,2,4-benzotriazine-1,4-dioxide,N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide,1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol.

[69] In another preferred embodiment, the present invention provides aprocess for the preparation of diagnostic or therapeuticmetallopharmaceutical composition, said process comprising generating amacrostructure from a plurality of molecular components wherein theplurality of components includes a targeting moiety and a chelator,wherein the targeting moiety is a peptide or peptidomimetic, which isbound to the chelator, and binds to a receptor that is upregulatedduring angiogenesis and the compound has 0-1 linking groups between thetargeting moiety and chelator.

Another embodiment of the present invention is diagnostic kits for thepreparation of radiopharmaceuticals useful as imaging agents for canceror imaging agents for imaging formation of new blood vessels. Diagnostickits of the present invention comprise one or more vials containing thesterile, non-pyrogenic, formulation comprised of a predetermined amountof a reagent of the present invention, and optionally other componentssuch as one or two ancillary ligands, reducing agents, transfer ligands,buffers, lyophilization aids, stabilization aids, solubilization aidsand bacteriostats. The inclusion of one or more optional components inthe formulation will frequently improve the ease of synthesis of theradiopharmaceutical by the practicing end user, the ease ofmanufacturing the kit, the shelf-life of the kit, or the stability andshelf-life of the radiopharmaceutical. The inclusion of one or twoancillary ligands is required for diagnostic kits comprising reagentcomprising a hydrazine or hydrazone bonding moiety. The one or morevials that contain all or part of the formulation can independently bein the form of a sterile solution or a lyophilized solid.

Another aspect of the present invention contemplates the combination ofchemotherapeutics and angiogenesis-targeted therapeuticradiopharmaceuticals of the invention, which target the luminal side ofthe neovasculature of tumors, to provide a surprising, and enhanceddegree of tumor suppression relative to each treatment modality alonewithout significant additive toxicity.

Another aspect of the present invention contemplates the compounds ofthe present invention (i.e. a compound comprising: a targeting moietyand a chelator, wherein the targeting moiety is bound to the chelator,is a peptide or peptidomimetic, and binds to a receptor that isupregulated during angiogenesis and the compound has 0-1 linking groupsbetween the targeting moiety and chelator) which is administered incombination therapy, with one or more chemotherapeutic agent(s) selectedfrom the group consisting of mitomycin, tretinoin, ribomustin,gemcitabine, vincristine, etoposide, cladribine, mitobronitol,methotrexate, doxorubicin, carboquone, pentostatin, nitracrine,zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole,fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine,bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine,proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate,isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil,butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol,tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide,improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen,progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha,interferon-2 alpha, interferon-beta, interferon-gamma, colonystimulating factor-1, colony stimulating factor-2, denileukin diftitox,interleukin-2, and leutinizing hormone releasing factor.

This combination therapy may further, optionally, include aradiosensitizer agent, or a pharmaceutically acceptable salt thereof, toenhance the radiotherapeutic effect together with the chemotherapeuticagent, said radiosensitizer agent being selected from the groupconsisting of2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide,N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine,3-amino-1,2,4-benzotriazine-1,4-dioxide,N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide,1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol. A thoroughdiscussion of radiosensitizer agents is provided in the following:Rowinsky-EK, Oncology-Huntingt., 1999 October; 13(10 Suppl 5): 61-70;Chen-AY et al., Oncology-Huntingt. 1999 October; 13(10 Suppl 5): 39-46;Choy-H, Oncology-Huntingt. 1999 October; 13(10 Suppl 5): 23-38; andHerscher-LL et al, Oncology-Huntingt. 1999 October; 13(10 Suppl 5):11-22, which are incorporated herein by reference.

It is a further aspect of the invention to provide kits having aplurality of active ingredients (with or without carrier) which,together, may be effectively utilized for carrying out the novelcombination therapies of the invention.

It is another aspect of the invention to provide a novel pharmaceuticalcomposition which is effective, in and of itself, for utilization in abeneficial combination therapy because it includes compounds of thepresent invention, and a chemotherapeutic agent or a radiosensitizeragent, which may be utilized in accordance with the invention.

In another aspect, the present invention provides a method for treatingcancer in a patient in need of such treatment, said method including thesteps of administering a therapeutically effective amount of a compoundof the present invention and administering a therapeutically effectiveamount of at least one agent selected from the group consisting of achemotherapeutic agent and a radiosensitizer agent.

It is to be understood that this invention covers all appropriatecombinations of the particular and preferred groupings and embodimentsreferred to herein.

DEFINITIONS

The compounds herein described may have asymmetric centers. Unlessotherwise indicated, all chiral, diastereomeric and racemic forms areincluded in the present invention. Many geometric isomers of olefins,C═N double bonds, and the like can also be present in the compoundsdescribed herein, and all such stable isomers are contemplated in thepresent invention. It will be appreciated that compounds of the presentinvention contain asymmetrically substituted carbon atoms, and may beisolated in optically active or racemic forms. It is well known in theart how to prepare optically active forms, such as by, resolution ofracemic forms or by synthesis from optically active starting materials.Two distinct isomers (cis and trans) of the peptide bond are known tooccur; both can also be present in the compounds described herein, andall such stable isomers are contemplated in the present invention. The Dand L-isomers of a particular amino acid are designated herein using theconventional 3-letter abbreviation of the amino acid, as indicated bythe following examples: D-Leu, or L-Leu.

When any variable occurs more than one time in any substituent or in anyformula, its definition on each occurrence is independent of itsdefinition at every other occurrence. Thus, for example, if a group isshown to be substituted with 0-2 R⁵², then said group may optionally besubstituted with up to two R⁵², and R⁵² at each occurrence is selectedindependently from the defined list of possible R⁵². Also, by way ofexample, for the group —N(R⁵³)₂, each of the two R⁵³ substituents on Nis independently selected from the defined list of possible R⁵³.Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. When a bond to asubstituent is shown to cross the bond connecting two atoms in a ring,then such substituent may be bonded to any atom on the ring.

By “reagent” is meant a compound of this invention capable of directtransformation into a metallopharmaceutical of this invention. Reagentsmay be utilized directly for the preparation of themetallopharmaceuticals of this invention or may be a component in a kitof this invention.

The term “binding agent” means a metallopharmaceutical of this inventionhaving affinity for and capable of binding to the vitronectin receptor.The binding agents of this invention preferably have Ki<1000 nM.

Metallopharmaceutical as used herein is intended to refer to apharmaceutically acceptable compound containing a metal, wherein thecompound is useful for imaging, magnetic resonance imaging, contrastimaging, or x-ray imaging. The metal is the cause of the imageablesignal in diagnostic applications and the source of the cytotoxicradiation in radiotherapeutic applications. Radiopharmaceuticals aremetallopharmaceuticals in which the metal is a radioisotope.

By “stable compound” or “stable structure” is meant herein a compoundthat is sufficiently robust to survive isolation to a useful degree ofpurity from a reaction mixture, and formulation into an efficaciouspharmaceutical agent.

The term “substituted”, as used herein, means that one or more hydrogenson the designated atom or group is replaced with a selection from theindicated group, provided that the designated atom's or group's normalvalency is not exceeded, and that the substitution results in a stablecompound. When a substituent is keto (i.e., ═O), then 2 hydrogens on theatom are replaced.

The term “bond”, as used herein, means either a single or double bond.

The term “salt”, as used herein, is used as defined in the CRC Handbookof Chemistry and Physics, 65th Edition, CRC Press, Boca Raton, Fla.,1984, as any substance which yields ions, other than hydrogen orhydroxyl ions. As used herein, “pharmaceutically acceptable salts” referto derivatives of the disclosed compounds modified by making acid orbase salts. Examples of pharmaceutically acceptable salts include, butare not limited to, mineral or organic acid salts of basic residues suchas amines; alkali or organic salts of acidic residues such as carboxylicacids; and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable prodrugs” as used herein meansthose prodrugs of the compounds useful according to the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” means compoundsthat are rapidly transformed in vivo to yield the parent compound of theabove formula, for example by hydrolysis in blood. Functional groupswhich may be rapidly transformed, by metabolic cleavage, in vivo form aclass of groups reactive with the carboxyl group of the compounds ofthis invention. They include, but are not limited to such groups asalkanoyl (such as acetyl, propionyl, butyryl, and the like),unsubstituted and substituted aroyl (such as benzoyl and substitutedbenzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (suchas trimethyl- and triethysilyl), monoesters formed with dicarboxylicacids (such as succinyl), and the like. Because of the ease with whichthe metabolically cleavable groups of the compounds useful according tothis invention are cleaved in vivo, the compounds bearing such groupsact as pro-drugs. The compounds bearing the metabolically cleavablegroups have the advantage that they may exhibit improved bioavailabilityas a result of enhanced solubility and/or rate of absorption conferredupon the parent compound by virtue of the presence of the metabolicallycleavable group. A thorough discussion of prodrugs is provided in thefollowing: Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985;Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42,p.309-396, 1985; A Textbook of Drug Design and Development,Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Design andApplications of Prodrugs” p.113-191, 1991; Advanced Drug DeliveryReviews, H. Bundgard, 8, p.1-38, 1992; Journal of PharmaceuticalSciences, 77, p. 285, 1988; Chem. Pharm. Bull., N. Nakeya et al, 32, p.692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V.Stella, Vol. 14 of the A.C.S. Symposium Series, and BioreversibleCarriers in Drug Design, Edward B. Roche, ed., American PharmaceuticalAssociation and Pergamon Press, 1987, which are incorporated herein byreference.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. C₁₋₁₀ alkyl, is intended to includeC₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl”is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more halogen (for example —C_(v)F_(w) wherev=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are notlimited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, andpentachloroethyl. “Alkoxy” represents an alkyl group as defined abovewith the indicated number of carbon atoms attached through an oxygenbridge. C₁₋₁₀ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇,C₈, C₉, and C₁₀ alkoxy groups. Examples of alkoxy include, but are notlimited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy,t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to includesaturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl.C₃₋₇ cycloalkyl, is intended to include C₃, C₄, C₅, C₆, and C₇cycloalkyl groups. Alkenyl” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedcarbon-carbon bonds which may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₁₀ alkenyl, is intended to include C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkenyl groups. “Alkynyl” isintended to include hydrocarbon chains of either a straight or branchedconfiguration and one or more triple carbon-carbon bonds which may occurin any stable point along the chain, such as ethynyl and propynyl. C₂₋₁₀alkynyl, is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀alkynyl groups.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl.

As used herein, the term “alkaryl” means an aryl group bearing an alkylgroup of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; the term“aralkyl” means an alkyl group of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10carbon atoms bearing an aryl group; the term “arylalkaryl” means an arylgroup bearing an alkyl group of 1-10 carbon atoms bearing an aryl group;and the term “heterocycloalkyl” means an alkyl group of 1, 2, 3, 4, 5,6, 7, 8, 9, or 10 carbon atoms bearing a heterocycle.

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1. Asused herein, the term “aromatic heterocyclic system” or “heteroaryl” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and 1, 2, 3, or 4 heterotams independentlyselected from the group consisting of N, NH, O and S. It is to be notedthat total number of S and O atoms in the aromatic heterocycle is notmore than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxodiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Preferred heterocycles include, but are not limited to,pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl,imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, andisatinoyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

A “polyalkylene glycol” is a polyethylene glycol, polypropylene glycolor polybutylene glycol having a molecular weight of less than about5000, terminating in either a hydroxy or alkyl ether moiety.

A “carbohydrate” is a polyhydroxy aldehyde, ketone, alcohol or acid, orderivatives thereof, including polymers thereof having polymericlinkages of the acetal type.

A “cyclodextrin” is a cyclic oligosaccharide. Examples of cyclodextrinsinclude, but are not limited to, α-cyclodextrin,hydroxyethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin,β-cyclodextrin, hydroxypropyl-β-cyclodextrin,carboxymethyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin,hydroxyethyl-β-cyclodextrin, 2,6 di-O-methyl-β-cyclodextrin,sulfated-β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin,dihydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, andsulfated γ-cyclodextrin.

As used herein, the term “polycarboxyalkyl” means an alkyl group havingbetween two and about 100 carbon atoms and a plurality of carboxylsubstituents; and the term “polyazaalkyl” means a linear or branchedalkyl group having between two and about 100 carbon atoms, interruptedby or substituted with a plurality of amine groups.

A “reducing agent” is a compound that reacts with a radionuclide, whichis typically obtained as a relatively unreactive, high oxidation statecompound, to lower its oxidation state by transferring electron(s) tothe radionuclide, thereby making it more reactive. Reducing agentsuseful in the preparation of radiopharmaceuticals and in diagnostic kitsuseful for the preparation of said radiopharmaceuticals include but arenot limited to stannous chloride, stannous fluoride, formamidinesulfinic acid, ascorbic acid, cysteine, phosphines, and cuprous orferrous salts. Other reducing agents are described in Brodack et. al.,PCT Application 94/22496, which is incorporated herein by reference.

A “transfer ligand” is a ligand that forms an intermediate complex witha metal ion that is stable enough to prevent unwanted side-reactions butlabile enough to be converted to a metallopharmaceutical. The formationof the intermediate complex is kinetically favored while the formationof the metallopharmaceutical is thermodynamically favored. Transferligands useful in the preparation of metallopharmaceuticals and indiagnostic kits useful for the preparation of diagnosticradiopharmaceuticals include but are not limited to gluconate,glucoheptonate, mannitol, glucarate,N,N,N′,N′-ethylenediaminetetraacetic acid, pyrophosphate andmethylenediphosphonate. In general, transfer ligands are comprised ofoxygen or nitrogen donor atoms.

The term “donor atom” refers to the atom directly attached to a metal bya chemical bond.

“Ancillary” or “co-ligands” are ligands that are incorporated into aradiopharmaceutical during its synthesis. They serve to complete thecoordination sphere of the radionuclide together with the chelator orradionuclide bonding unit of the reagent. For radiopharmaceuticalscomprised of a binary ligand system, the radionuclide coordinationsphere is composed of one or more chelators or bonding units from one ormore reagents and one or more ancillary or co-ligands, provided thatthere are a total of two types of ligands, chelators or bonding units.For example, a radiopharmaceutical comprised of one chelator or bondingunit from one reagent and two of the same ancillary or co-ligands and aradiopharmaceutical comprised of two chelators or bonding units from oneor two reagents and one ancillary or co-ligand are both considered to becomprised of binary ligand systems. For radiopharmaceuticals comprisedof a ternary ligand system, the radionuclide coordination sphere iscomposed of one or more chelators or bonding units from one or morereagents and one or more of two different types of ancillary orco-ligands, provided that there are a total of three types of ligands,chelators or bonding units. For example, a radiopharmaceutical comprisedof one chelator or bonding unit from one reagent and two differentancillary or co-ligands is considered to be comprised of a ternaryligand system.

Ancillary or co-ligands useful in the preparation ofradiopharmaceuticals and in diagnostic kits useful for the preparationof said radiopharmaceuticals are comprised of one or more oxygen,nitrogen, carbon, sulfur, phosphorus, arsenic, selenium, and telluriumdonor atoms. A ligand can be a transfer ligand in the synthesis of aradiopharmaceutical and also serve as an ancillary or co-ligand inanother radiopharmaceutical. Whether a ligand is termed a transfer orancillary or co-ligand depends on whether the ligand remains in theradionuclide coordination sphere in the radiopharmaceutical, which isdetermined by the coordination chemistry of the radionuclide and thechelator or bonding unit of the reagent or reagents.

A “chelator” or “bonding unit” is the moiety or group on a reagent thatbinds to a metal ion through the formation of chemical bonds with one ormore donor atoms.

The term “binding site” means the site in vivo or in vitro that binds abiologically active molecule.

A “diagnostic kit” or “kit” comprises a collection of components, termedthe formulation, in one or more vials which are used by the practicingend user in a clinical or pharmacy setting to synthesize diagnosticradiopharmaceuticals. The kit provides all the requisite components tosynthesize and use the diagnostic radiopharmaceutical except those thatare commonly available to the practicing end user, such as water orsaline for injection, a solution of the radionuclide, equipment forheating the kit during the synthesis of the radiopharmaceutical, ifrequired, equipment necessary for administering the radiopharmaceuticalto the patient such as syringes and shielding, and imaging equipment.

Therapeutic radiopharmaceuticals, X-ray contrast agent pharmaceuticals,ultrasound contrast agent pharmaceuticals and metallopharmaceuticals formagnetic resonance imaging contrast are provided to the end user intheir final form in a formulation contained typically in one vial, aseither a lyophilized solid or an aqueous solution. The end userreconstitutes the lyophilized with water or saline and withdraws thepatient dose or just withdraws the dose from the aqueous solutionformulation as provided.

A “lyophilization aid” is a component that has favorable physicalproperties for lyophilization, such as the glass transition temperature,and is added to the formulation to improve the physical properties ofthe combination of all the components of the formulation forlyophilization.

A “stabilization aid” is a component that is added to themetallopharmaceutical or to the diagnostic kit either to stabilize themetallopharmaceutical or to prolong the shelf-life of the kit before itmust be used. Stabilization aids can be antioxidants, reducing agents orradical scavengers and can provide improved stability by reactingpreferentially with species that degrade other components or themetallopharmaceutical.

A “solubilization aid” is a component that improves the solubility ofone or more other components in the medium required for the formulation.

A “bacteriostat” is a component that inhibits the growth of bacteria ina formulation either during its storage before use of after a diagnostickit is used to synthesize a radiopharmaceutical.

The term “amino acid” as used herein means an organic compoundcontaining both a basic amino group and an acidic carboxyl group.Included within this term are natural amino acids (e.g., L-amino acids),modified and unusual amino acids (e.g., D-amino acids), as well as aminoacids which are known to occur biologically in free or combined form butusually do not occur in proteins. Included within this term are modifiedand unusual amino acids, such as those disclosed in, for example,Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching ofwhich is hereby incorporated by reference. Natural protein occurringamino acids include, but are not limited to, alanine, arginine,asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine,histidine, isoleucine, leucine, lysine, methionine, phenylalanine,serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine.Natural non-protein amino acids include, but are not limited toarginosuccinic acid, citrulline, cysteine sulfinic acid,3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine,3-monoiodotyrosine, 3,5-diiodotryosine, 3,5,5′-triiodothyronine, and3,3′,5,5′-tetraiodothyronine. Modified or unusual amino acids which canbe used to practice the invention include, but are not limited to,D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected aminoacid, 2,4-diaminobutyric acid, homoarginine, norleucine,N-methylaminobutyric acid, naphthylalanine, phenylglycine,β-phenylproline, tert-leucine, 4-aminocyclohexylalanine,N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine,N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid,6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid,2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylicacid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoicacid.

The term “peptide” as used herein means a linear compound that consistsof two or more amino acids (as defined herein) that are linked by meansof a peptide bond. A “peptide” as used in the presently claimedinvention is intended to refer to a moiety with a molecular weight ofless than 10,000 Daltons, preferable less than 5,000 Daltons, and morepreferably less than 2,500 Daltons. The term “peptide” also includescompounds containing both peptide and non-peptide components, such aspseudopeptide or peptidomimetic residues or other non-amino acidcomponents. Such a compound containing both peptide and non-peptidecomponents may also be referred to as a “peptide analog”.

A “pseudopeptide” or “peptidomimetic” is a compound which mimics thestructure of an amino acid residue or a peptide, for example, by usinglinking groups other than amide linkages between the peptide mimetic andan amino acid residue (pseudopeptide bonds) and/or by using non-aminoacid substituents and/or a modified amino acid residue. A “pseudopeptideresidue” means that portion of an pseudopeptide or peptidomimetic thatis present in a peptide.

The term “peptide bond” means a covalent amide linkage formed by loss ofa molecule of water between the carboxyl group of one amino acid and theamino group of a second amino acid.

The term “pseudopeptide bonds” includes peptide bond isosteres which maybe used in place of or as substitutes for the normal amide linkage.These substitute or amide “equivalent” linkages are formed fromcombinations of atoms not normally found in peptides or proteins whichmimic the spatial requirements of the amide bond and which shouldstabilize the molecule to enzymatic degradation.

The following abbreviations are used herein:

Acm acetamidomethyl b-Ala, beta-Ala 3-aminopropionic acid or bAla ATA2-aminothiazole-5-acetic acid or 2- aminothiazole-5-acetyl group Boct-butyloxycarbonyl CBZ, Cbz or Z Carbobenzyloxy Cit citrulline Dap2,3-diaminopropionic acid DCC dicyclohexylcarbodiimide DIEAdiisopropylethylamine DMAP 4-dimethylaminopyridine EOE ethoxyethyl HBTU2-(1H-Benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphatehynic boc-hydrazinonicotinyl group or 2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]- benzenesulfonic acid, NMeArgor MeArg a-N-methyl arginine NMeAsp a-N-methyl aspartic acid NMMN-methylmorpholine OcHex O-cyclohexyl OBzl O-benzyl oSu O-succinimidylTBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3- tetramethyluroniumtetrafluoroborate THF tetrahydrofuranyl THP tetrahydropyranyl Tos tosylTr trityl

The following conventional three-letter amino acid abbreviations areused herein; the conventional one-letter amino acid abbreviations areNOT used herein:

Ala = alanine Arg = arginine Asn = asparagine Asp = aspartic acid Cys =cysteine Gln = glutamine Glu = glutamic acid Gly = glycine His =histidine Ile = isoleucine Leu = leucine Lys = lysine Met = methionineNle = norleucine Orn = ornithine Phe = phenylalanine Phg = phenylglycinePro = proline Sar = sarcosine Ser = serine Thr = threonine Trp =tryptophan Tyr = tyrosine Val = valine

The pharmaceuticals of the present invention are comprised of atargeting moiety for a receptor that is expressed or upregulated inangiogenic tumor vasculature. For targeting the VEGF receptors,Flk-1/KDR, Flt-1, and neuropilin-1, the targeting moieties are comprisedof peptides or peptidomimetics that bind with high affinity to thereceptors. For example, peptides comprised of a 23 amino acid portion ofthe C-terminal domain of VEGF have been synthesized which competitivelyinhibit binding of VEGF to VEGFR (Soker, et. al., J. Biol. Chem., 1997,272, 31582-8). Linear peptides of 11 to 23 amino acid residues that bindto the basic FGF receptor (bFGFR) are described by Cosic et. al., Mol.and Cell. Biochem., 1994, 130, 1-9. A preferred linear peptideantagonist of the bFGFR is the 16 amino acid peptide,Met-Trp-Tyr-Arg-Pro-Asp-Leu-Asp-Glu-Arg-Lys-Gln-Gln-Lys-Arg-Glu. Gho et.al. (Cancer Research, 1997, 57, 3733-40) describe the identification ofsmall peptides that bind with high affinity to the angiogenin receptoron the surface of endothelial cells. A preferred peptide isAla-Gln-Leu-Ala-Gly-Glu-Cys-Arg-Glu-Asn-Val-Cys-Met-Gly-Ile-Glu-Gly-Arg,in which the two Cys residues form an intramolecular disulfide bond.Yayon et. al. (Proc. Natl. Acad. Sci, USA, 1993, 90, 10643-7) describeother linear peptide antagonists of FGFR, identified from a randomphage-displayed peptide library. Two linear octapeptides,Ala-Pro-Ser-Gly-His-Tyr-Lys-Gly and Lys-Arg-Thr-Gly-Gln-Tyr-Lys-Leu arepreferred for inhibiting binding of bFGF to it receptor.

Targeting moieties for integrins expressed in tumor vasculature includepeptides and peptidomimetics that bind to α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁,α₁β₁, and α₂β₂. Pierschbacher and Rouslahti (J. Biol. Chem., 1987, 262,17294-8) describe peptides that bind selectively to α₅β₁ and α_(v)β₃.U.S. Pat. No. 5,536,814 describe peptides that bind with high affinityto the integrin α₅β₁. Burgess and Lim (J. Med. Chem., 1996, 39, 4520-6)disclose the synthesis three peptides that bind with high affinity toα_(v)β₃: cyclo[Arg-Gly-Asp-Arg-Gly-Asp],cyclo[Arg-Gly-Asp-Arg-Gly-D-Asp] and the linear peptideArg-Gly-Asp-Arg-Gly-Asp. U.S. Pat. Nos. 5,770,565 and 5,766,591 disclosepeptides that bind with high affinity to α_(v)β₃. U.S. Pat. Nos.5,767,071 and 5,780,426, disclose cyclic peptides that have an exocyclicArg amino acid that have high affinity for α_(v)β₃. Srivatsa et. al.,(Cardiovascular Res., 1997, 36, 408-28) describe the cyclic peptideantagonist for α_(v)β₃, cyclo[Ala-Arg-Gly-Asp-Mamb]. Tran et. al.,(Bioorg. Med. Chem. Lett., 1997, 7, 997-1002) disclose the cyclicpeptide cyclo[Arg-Gly-Asp-Val-Gly-Ser-BTD-Ser-Gly-Val-Ala] that bindswith high affinity to α_(v)β₃. Arap et. al. (Science, 1998, 279, 377-80)describe cyclic peptides that bind to α_(v)β₃ and α_(v)β₅,Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys, and cyclo[Cys-Asn-Gly-Asp-Cys].Corbett et. al. (Biorg. Med. Chem. Lett., 1997, 7, 1371-6) describe aseries of α_(v)β₃ selective peptidomimetics. And Haubner et. al.,(Angew. Chem. Int. Ed. Engl., 1997, 36, 1374-89) disclose peptides andpeptidomimetic α_(v)β₃ antagonists obtained from peptide libraries.

The targeting moieties of the present invention, preferably, have abinding affinity for the integrin α_(v)β₃ of less than 1000 nM. Morepreferably, the targeting moieties of the present invention, preferably,have a binding affinity for the integrin α_(v)β₃ of less than 100 nM.Even more preferably, the targeting moieties of the present invention,preferably, have a binding affinity for the integrin α_(v)β₃ of lessthan 10 nM.

The ultrasound contrast agents of the present invention comprise aplurality of angiogenic tumor vasculature targeting moieties attached toor incorporated into a microbubble of a biocompatible gas, a liquidcarrier, and a surfactant microsphere, further comprising an optionallinking moiety, L_(n), between the targeting moieties and themicrobubble. In this context, the term liquid carrier means aqueoussolution and the term surfactant means any amphiphilic material whichproduces a reduction in interfacial tension in a solution. A list ofsuitable surfactants for forming surfactant microspheres is disclosed inEP0727225A2, herein incorporated by reference. The term surfactantmicrosphere includes nanospheres, liposomes, vesicles and the like. Thebiocompatible gas can be air, or a fluorocarbon, such as a C₃-C₅perfluoroalkane, for example, perflouropropane, perflourobutane, orperflouropentane, which provides the difference in echogenicity and thusthe contrast in ultrasound imaging. The gas is encapsulated or containedin the microsphere to which is attached the biodirecting group,optionally via a linking group. The attachment can be covalent, ionic orby van der Waals forces. Specific examples of such contrast agentsinclude lipid encapsulated perfluorocarbons with a plurality of tumorneovasculature receptor binding peptides or peptidomimetics.

S_(f) as used herein is a surfactant which is either a lipid or acompound of the formula A¹-E-A², defined above. The surfactant isintended to form a vesicle (e.g., a microsphere) capable of containingan echogenic gas. The ultrasound contrast agent compositions of thepresent invention are intended to be capable upon agitation (e.g.,shaking, stirring, etc . . . ) of encapsulating an echogenic gas in avescicle in such a way as to allow for the resultant product to beuseful as an ultrasound contrast agent.

“Vesicle” refers to a spherical entity which is characterized by thepresence of an internal void. Preferred vesicles are formulated fromlipids, including the various lipids described herein. In any givenvesicle, the lipids may be in the form of a monolayer or bilayer, andthe mono- or bilayer lipids may be used to form one of more mono- orbilayers. In the case of more than one mono- or bilayer, the mono- orbilayers are generally concentric. The lipid vesicles described hereininclude such entities commonly referred to as liposomes, micelles,bubbles, microbubbles, microspheres and the like. Thus, the lipids maybe used to form a unilamellar vesicle (comprised of one monolayer orbilayer), an oligolamellar vesicle (comprised of about two or aboutthree monolayers or bilayers) or a multilamellar vesicle (comprised ofmore than about three monolayers or bilayers). The internal void of thevesicles may be filled with a liquid, including, for example, an aqueousliquid, a gas, a gaseous precursor, and/or a solid or solute material,including, for example, a bioactive agent, as desired.

“Vesicular composition” refers to a composition which is formulate fromlipids and which comprises vesicles.

“Vesicle formulation” refers to a composition which comprises vesiclesand a bioactive agent.

Microsphere, as used herein, is preferably a sphere of less than orequal to 10 microns. Liposome, as used herein, may include a singlelipid layer (a lipid monolayer), two lipid layers (a lipid bilayer) ormore than two lipid layers (a lipid multilayer). “Lipsomes” refers to agenerally spherical cluster or aggregate of amphipathic compounds,including lipid compounds, typically in the form of one or moreconcentric layers, for example, bilayers. They may also be referred toherein as lipid vesicles.

The term “bubbles”, as used herein, refers to vesicles which aregenerally characterized by the presence of one or more membranes orwalls surrounding an internal void that is filled with a gas orprecursor thereto. Exemplary bubbles include, for example, liposomes,micelles and the like.

“Lipid” refers to a synthetic or naturally-occurring amphipathiccompound which comprises a hydrophilic component and a hydrophobiccomponent. Lipids include, for example, fatty acids, neutral fats,phosphatides, glycolipids, aliphatic alchols and waxes, terpenes andsteroids.

“Lipid composition” refers to a composition which comprises a lipidcompound. Exemplary lipid compositions include suspensions, emulsionsand vesicular compositions.

“Lipid formulation” refers to a composition which comprises a lipidcompound and a bioactive agent.

Examples of classes of suitable lipids and specific suitable lipidsinclude: phosphatidylcholines, such as dioleoylphosphatidylcholine,dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC),and distearoylphosphatidylcholine; phosphatidylethanolamines, such asdipalmitoylphosphatidylethanolamine (DPPE),dioleoylphosphatidylethanolamine andN-succinyl-dioleoylphosphatidylethanolamine; phosphatidylserines;phosphatidylglycerols; sphingolipids; glycolipids, such as gangliosideGM1; glucolipids; sulfatides; glycosphingolipids; phosphatidic acids,such as dipalmatoylphosphatidic acid (DPPA); palmitic fatty acids;stearic fatty acids; arachidonic fatty acids; lauric fatty acids;myristic fatty acids; lauroleic fatty acids; physeteric fatty acids;myristoleic fatty acids; palmitoleic fatty acids; petroselinic fattyacids; oleic fatty acids; isolauric fatty acids; isomyristic fattyacids; isopalmitic fatty acids; isostearic fatty acids; cholesterol andcholesterol derivatives, such as cholesterol hemisuccinate, cholesterolsulfate, and cholesteryl-(4′-trimethylammonio)-butanoate;polyoxyethylene fatty acid esters; polyoxyethylene fatty acid alcohols;polyoxyethylene fatty acid alcohol ethers; polyoxyethylated sorbitanfatty acid esters; glycerol polyethylene glycol oxystearate; glycerolpolyethylene glycol ricinoleate; ethoxylated soybean sterols;ethoxylated castor oil; polyoxyethylene-polyoxypropylene fatty acidpolymers; polyoxyethylene fatty acid stearates;12-(((7′-diethylaminocoumarin-3-yl)-carbonyl)-methylamino)-octadecanoicacid;N-[12-(((7′-diethylamino-coumarin-3-yl)-carbonyl)-methylamino)octadecanoyl]-2-amino-palmiticacid; 1,2-dioleoyl-sn-glycerol; 1,2-dipalmitoyl-sn-3-succinylglycerol;1,3-dipalmitoyl-2-succinyl-glycerol; and1-hexadecyl-2-palmitoyl-glycerophosphoethanolamine andpalmitoylhomocysteine; lauryltrimethylammonium bromide;cetyltrimethylammonium bromide; myristyltrimethylammonium bromide;alkyldimethylbenzylammonium chlorides, such as wherein alkyl is a C₁₂,C₁₄ or C₁₆ alkyl; benzyldimethyldodecylammonium bromide;benzyldimethyldodecylammonium chloride, benzyldimethylhexadecylammoniumbromide; benzyldimethylhexadecylammonium chloride;benzyldimethyltetradecylammonium bromide;benzyldimethyltetradecylammonium chloride; cetyldimethylethylammoniumbromide; cetyldimethylethylammonium chloride; cetylpyridinium bromide;cetylpyridinium chloride;N-[1,2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA);1,2-dioleoyloxy-3-(trimethylammonio)propane (DOTAP); and1,2-dioleoyl-c-(4′-trimethylammonio)-butanoyl-sn-glycerol (DOTB).

The echogenic gas may be one gas or mixture of gases, such as CF₄, C₂F₆,C₃F₈, cyclo-C₄F₈, C₄F₁₀, C₅F₁₂, cyclo-C₅F₁₀, cyclo-C₄F₇(1-trifluoromethyl), propane(2-trifluoromethyl)-1,1,1,3,3,3 hexafluoro,and butane(2-trifluoromethyl)-1,1,1,3,3,3,4,4,4 nonafluoro. Alsopreferred are the the corresponding unsaturated versions of the abovecompounds, for example C₂F₄, C₃F₆, the isomers of C₄F₈. Also, mixturesof these gases, especially mixtures of perfluorocarbons with otherperfluorocarbons and mixtures of perfluorocarbons with other inertgases, such as air, N₂, O₂, He, would be useful. Examples of these canbe found in Quay, U.S. Pat. No. 5,595,723, the contents of which areherein incorporated by reference.

X-ray contrast agents of the present invention are comprised of one ormore angiogenic tumor vasculature targeting moieties attached to one ormore X-ray absorbing or “heavy” atoms of atomic number 20 or greater,further comprising an optional linking moiety, L_(n), between thetargeting moieties and the X-ray absorbing atoms. The frequently usedheavy atom in X-ray contrast agents is iodine. Recently, X-ray contrastagents comprised of metal chelates (Wallace, R., U.S. Pat. No.5,417,959) and polychelates comprised of a plurality of metal ions(Love, D., U.S. Pat. No. 5,679,810) have been disclosed. More recently,multinuclear cluster complexes have been disclosed as X-ray contrastagents (U.S. Pat. No. 5,804,161, PCT WO91/14460, and PCT WO 92/17215).Examples of X-ray agents include the non-radioactive or naturallyoccurring analogs of the above listed radionuclides (e.g., Re, Sm, Ho,Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir).

MRI contrast agents of the present invention are comprised of one ormore angiogenic tumor vasculature targeting moieties attached to one ormore paramagnetic metal ions, further comprising an optional linkingmoiety, L_(n), between the targeting moieties and the paramagnetic metalions. The paramagnetic metal ions are present in the form of metalcomplexes or metal oxide particles. U.S. Pat. Nos. 5,412,148, and5,760,191, describe examples of chelators for paramagnetic metal ionsfor use in MRI contrast agents. U.S. Pat. Nos. 5,801,228, 5,567,411, and5,281,704, describe examples of polychelants useful for complexing morethan one paramagnetic metal ion for use in MRI contrast agents. U.S.Pat. No. 5,520,904, describes particulate compositions comprised ofparamagnetic metal ions for use as MRI contrast agents.

Administration of a compound of the present invention in combinationwith such additional therapeutic agents, may afford an efficacyadvantage over the compounds and agents alone, and may do so whilepermitting the use of lower doses of each. A lower dosage minimizes thepotential of side effects, thereby providing an increased margin ofsafety. The combination of a compound of the present invention with suchadditional therapeutic agents is preferably a synergistic combination.Synergy, as described for example by Chou and Talalay, Adv. EnzymeRegul. 22:27-55 (1984), occurs when the therapeutic effect of thecompound and agent when administered in combination is greater than theadditive effect of the either the compound or agent when administeredalone. In general, a synergistic effect is most clearly demonstrated atlevels that are (therapeutically) sub-optimal for either the compound ofthe present invention, a chemotherapeutic agent or a radiosensitizeragent alone, but which are highly efficacious in combination. Synergycan be in terms of improved tumor response without substantial increasesin toxicity over individual treatments alone, or some other beneficialeffect of the combination compared with the individual components.

The compounds of the present invention, and a chemotherapeutic agent ora radiosensitizer agent, utilized in combination therapy may beadministered simultaneously, in either separate or combinedformulations, or at different times e.g., sequentially, such that acombined effect is achieved. The amounts and regime of administrationwill be adjusted by the practitioner, by preferably initially loweringtheir standard doses and then titrating the results obtained.

The invention also provides kits or single packages combining two ormore active ingredients useful in treating cancer. A kit may provide(alone or in combination with a pharmaceutically acceptable diluent orcarrier), the compound of the present invention and additionally atleast one agent selected from the group consisting of a chemotherapeuticagent and a radiosensitizer agent (alone or in combination with diluentor carrier).

The pharmaceuticals of the present invention have the formulae,(Q)_(d)—L_(n)—(C_(h)—X), (Q)_(d)—L_(n)—(C_(h)—X¹)_(d′),(Q)_(d)—L_(n)—(X²)_(d″), and (Q)_(d)—L_(n)—(X³), wherein Q represents apeptide or peptidomimetic that binds to a receptor expressed inangiogenic tumor vasculature, d is 1-10, L_(n) represents an optionallinking group, C_(h) represents a metal chelator or bonding moiety, Xrepresents a radioisotope, X¹ represents paramagnetic metal ion, X²represents a paramagnetic metal ion or heavy atom containing insolublesolid particle, d″ is 1-100, and X³ represents a surfactant microsphereof an echogenic gas. Preferred pharmaceuticals of the present inventionare comprised of targeting moieties, Q, that are peptides andpeptidomimetics that bind to the vitronectin receptors α_(v)β₃ andα_(v)β₅. More preferred pharmaceuticals of the present invention arecomprised of targeting moieties, Q, that are peptides andpeptidomimetics that bind to α_(v)β₃. Most preferred pharmaceuticals ofthe present invention are comprised of α_(v)β₃ targeting moieties, Q,that are comprised of one to ten cyclic pentapeptides orpeptidomimetics, independently attached to a therapeutic radioisotope orimageable moiety, further comprising an optional linking moiety, L_(n),between the targeting moieties and the therapeutic radioisotopes orimageable moieties. The cyclic peptides are comprised of a tripeptidesequence that binds to the α_(v)β₃ receptor and two amino acids eitherone of which can be attached to L_(n), C_(h), X², or X³. The interactionof the tripeptide recognition sequences of the cyclic peptide orpeptidomimetic portion of the pharmaceuticals with the α_(v)β₃ receptorresults in localization of the pharmaceuticals in angiogenic tumorvasculature, which express the α_(v)β₃ receptor.

The pharmaceuticals of the present invention can be synthesized byseveral approaches. One approach involves the synthesis of the targetingpeptide or peptidomimetic moiety, Q, and direct attachment of one ormore moieties, Q, to one or more metal chelators or bonding moieties,C_(h), or to a paramagnetic metal ion or heavy atom containing solidparticle, or to an echogenic gas microbubble. Another approach involvesthe attachment of one or more moieties, Q, to the linking group, L_(n),which is then attached to one or more metal chelators or bondingmoieties, C_(h), or to a paramagnetic metal ion or heavy atom containingsolid particle, or to an echogenic gas microbubble. Another approach,useful in the synthesis of pharmaceuticals wherein d is 1, involves thesynthesis of the moiety, Q—L_(n), together, by incorporating an aminoacid or amino acid mimetic residue bearing L_(n) into the synthesis ofthe peptide or peptidomimetic. The resulting moiety, Q—L_(n), is thenattached to one or more metal chelators or bonding moieties, C_(h), orto a paramagnetic metal ion or heavy atom containing solid particle, orto an echogenic gas microbubble. Another approach involves the synthesisof a peptide or peptidomimetic, Q, bearing a fragment of the linkinggroup, L_(n), one or more of which are then attached to the remainder ofthe linking group and then to one or more metal chelators or bondingmoieties, C_(h), or to a paramagnetic metal ion or heavy atom containingsolid particle, or to an echogenic gas microbubble.

The peptides or peptidomimetics, Q, optionally bearing a linking group,L_(n), or a fragment of the linking group, can be synthesized usingstandard synthetic methods known to those skilled in the art. Preferredmethods include but are not limited to those methods described below.

Generally, peptides and peptidomimetics are elongated by deprotectingthe alpha-amine of the C-terminal residue and coupling the next suitablyprotected amino acid through a peptide linkage using the methodsdescribed. This deprotection and coupling procedure is repeated untilthe desired sequence is obtained. This coupling can be performed withthe constituent amino acids in a stepwise fashion, or condensation offragments (two to several amino acids), or combination of bothprocesses, or by solid phase peptide synthesis according to the methodoriginally described by Merrifield, J. Am. Chem. Soc., 85, 2149-2154(1963), the disclosure of which is hereby incorporated by reference.

The peptides and peptidomimetics may also be synthesized using automatedsynthesizing equipment. In addition to the foregoing, procedures forpeptide and peptidomimetic synthesis are described in Stewart and Young,“Solid Phase Peptide Synthesis”, 2nd ed, Pierce Chemical Co., Rockford,Ill. (1984); Gross, Meienhofer, Udenfriend, Eds., “The Peptides:Analysis, Synthesis, Biology, Vol. 1, 2, 3, 5, and 9, Academic Press,New York, (1980-1987); Bodanszky, “Peptide Chemistry: A PracticalTextbook”, Springer-Verlag, New York (1988); and Bodanszky et al. “ThePractice of Peptide Synthesis” Springer-Verlag, New York (1984), thedisclosures of which are hereby incorporated by reference.

The coupling between two amino acid derivatives, an amino acid and apeptide or peptidomimetic, two peptide or peptidomimetic fragments, orthe cyclization of a peptide or peptidomimetic can be carried out usingstandard coupling procedures such as the azide method, mixed carbonicacid anhydride (isobutyl chloroformate) method, carbodiimide(dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-solublecarbodiimides) method, active ester (p-nitrophenyl ester,N-hydroxysuccinic imido ester) method, Woodward reagent K method,carbonyldiimidazole method, phosphorus reagents such as BOP-Cl, oroxidation-reduction method. Some of these methods (especially thecarbodiimide) can be enhanced by the addition of 1-hydroxybenzotriazole.These coupling reactions may be performed in either solution (liquidphase) or solid phase.

The functional groups of the constituent amino acids or amino acidmimetics must be protected during the coupling reactions to avoidundesired bonds being formed. The protecting groups that can be used arelisted in Greene, “Protective Groups in Organic Synthesis” John Wiley &Sons, New York (1981) and “The Peptides: Analysis, Synthesis, Biology,Vol. 3, Academic Press, New York (1981), the disclosure of which ishereby incorporated by reference.

The alpha-carboxyl group of the C-terminal residue is usually protectedby an ester that can be cleaved to give the carboxylic acid. Theseprotecting groups include: 1) alkyl esters such as methyl and t-butyl,2) aryl esters such as benzyl and substituted benzyl, or 3) esters whichcan be cleaved by mild base treatment or mild reductive means such astrichloroethyl and phenacyl esters. In the solid phase case, theC-terminal amino acid is attached to an insoluble carrier (usuallypolystyrene). These insoluble carriers contain a group which will reactwith the carboxyl group to form a bond which is stable to the elongationconditions but readily cleaved later. Examples of which are: oxime resin(DeGrado and Kaiser (1980) J. Org. Chem. 45, 1295-1300) chloro orbromomethyl resin, hydroxymethyl resin, and aminomethyl resin. Many ofthese resins are commercially available with the desired C-terminalamino acid already incorporated.

The alpha-amino group of each amino acid must be protected. Anyprotecting group known in the art can be used. Examples of these are: 1)acyl types such as formyl, trifluoroacetyl, phthalyl, andp-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl(Cbz) and substituted benzyloxycarbonyls,1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl(Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl(Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl;4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl andadamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl;6) trialkylsilane such as trimethylsilane; and 7) thiol containing typessuch as phenylthiocarbonyl and dithiasuccinoyl. The preferredalpha-amino protecting group is either Boc or Fmoc. Many amino acid oramino acid mimetic derivatives suitably protected for peptide synthesisare commercially available.

The alpha-amino protecting group is cleaved prior to the coupling of thenext amino acid. When the Boc group is used, the methods of choice aretrifluoroacetic acid, neat or in dichloromethane, or HCl in dioxane. Theresulting ammonium salt is then neutralized either prior to the couplingor in situ with basic solutions such as aqueous buffers, or tertiaryamines in dichloromethane or dimethylformamide. When the Fmoc group isused, the reagents of choice are piperidine or substituted piperidinesin dimethylformamide, but any secondary amine or aqueous basic solutionscan be used. The deprotection is carried out at a temperature between 0°C. and room temperature.

Any of the amino acids or amino acid mimetics bearing side chainfunctionalities must be protected during the preparation of the peptideusing any of the above-identified groups. Those skilled in the art willappreciate that the selection and use of appropriate protecting groupsfor these side chain functionalities will depend upon the amino acid oramino acid mimetic and presence of other protecting groups in thepeptide or peptidomimetic. The selection of such a protecting group isimportant in that it must not be removed during the deprotection andcoupling of the alpha-amino group.

For example, when Boc is chosen for the alpha-amine protection thefollowing protecting groups are acceptable: p-toluenesulfonyl (tosyl)moieties and nitro for arginine; benzyloxycarbonyl, substitutedbenzyloxycarbonyls, tosyl or trifluoroacetyl for lysine; benzyl or alkylesters such as cyclopentyl for glutamic and aspartic acids; benzylethers for serine and threonine; benzyl ethers, substituted benzylethers or 2-bromobenzyloxycarbonyl for tyrosine; p-methylbenzyl,p-methoxybenzyl, acetamidomethyl, benzyl, or t-butylsulfonyl forcysteine; and the indole of tryptophan can either be left unprotected orprotected with a formyl group.

When Fmoc is chosen for the alpha-amine protection usually tert-butylbased protecting groups are acceptable. For instance, Boc can be usedfor lysine, tert-butyl ether for serine, threonine and tyrosine, andtert-butyl ester for glutamic and aspartic acids.

Once the elongation of the peptide or peptidomimetic, or the elongationand cyclization of a cyclic peptide or peptidomimetic is completed allof the protecting groups are removed. For the liquid phase synthesis theprotecting groups are removed in whatever manner as dictated by thechoice of protecting groups. These procedures are well known to thoseskilled in the art.

When a solid phase synthesis is used to synthesize a cyclic peptide orpeptidomimetic, the peptide or peptidomimetic should be removed from theresin without simultaneously removing protecting groups from functionalgroups that might interfere with the cyclization process. Thus, if thepeptide or peptidomimetic is to be cyclized in solution, the cleavageconditions need to be chosen such that a free a-carboxylate and a freea-amino group are generated without simultaneously removing otherprotecting groups. Alternatively, the peptide or peptidomimetic may beremoved from the resin by hydrazinolysis, and then coupled by the azidemethod. Another very convenient method involves the synthesis ofpeptides or peptidomimetics on an oxime resin, followed byintramolecular nucleophilic displacement from the resin, which generatesa cyclic peptide or peptidomimetic (Osapay, Profit, and Taylor (1990)Tetrahedron Letters 43, 6121-6124). When the oxime resin is employed,the Boc protection scheme is generally chosen. Then, the preferredmethod for removing side chain protecting groups generally involvestreatment with anhydrous HF containing additives such as dimethylsulfide, anisole, thioanisole, or p-cresol at 0° C. The cleavage of thepeptide or peptidomimetic can also be accomplished by other acidreagents such as trifluoromethanesulfonic acid/trifluoroacetic acidmixtures.

Unusual amino acids used in this invention can be synthesized bystandard methods familiar to those skilled in the art (“The Peptides:Analysis, Synthesis, Biology, Vol. 5, pp. 342-449, Academic Press, NewYork (1981)). N-Alkyl amino acids can be prepared using proceduresdescribed in previously (Cheung et al., (1977) Can. J. Chem. 55, 906;Freidinger et al., (1982) J. Org. Chem. 48, 77 (1982)), which areincorporated herein by reference.

Additional synthetic procedures that can be used by one of skill in theart to synthesize the peptides and peptidomimetics targeting moietiesare described in PCT WO94/22910, the contents of which are hereinincorporated by reference.

The attachment of linking groups, L_(n), to the peptides andpeptidomimetics, Q; chelators or bonding units, C_(h), to the peptidesand peptidomimetics, Q, or to the linking groups, L_(n); and peptidesand peptidomimetics bearing a fragment of the linking group to theremainder of the linking group, in combination forming the moiety,(Q)_(d)—L_(n), and then to the moiety C_(h); can all be performed bystandard techniques. These include, but are not limited to, amidation,esterification, alkylation, and the formation of ureas or thioureas.Procedures for performing these attachments can be found in Brinkley,M., Bioconjugate Chemistry 1992, 3(1), which is incorporated herein byreference.

A number of methods can be used to attach the peptides andpeptidomimetics, Q, to paramagnetic metal ion or heavy atom containingsolid particles, X², by one of skill in the art of the surfacemodification of solid particles. In general, the targeting moiety Q orthe combination (Q)_(d)L_(n) is attached to a coupling group that reactwith a constituent of the surface of the solid particle. The couplinggroups can be any of a number of silanes which react with surfacehydroxyl groups on the solid particle surface, as described inco-pending U.S. A. No. 60/092,360, and can also includepolyphosphonates, polycarboxylates, polyphosphates or mixtures thereofwhich couple with the surface of the solid particles, as described inU.S. Pat. No. 5,520,904.

A number of reaction schemes can be used to attach the peptides andpeptidomimetics, Q, to the surfactant microsphere, X³. These areillustrated in following reaction schemes where S_(f) represents asurfactant moiety that forms the surfactant microsphere.

Acylation Reaction:

Y is a leaving group or active ester

Disulfide Coupling:

S_(f)—SH+Q—SH→S_(f)—S—S—Q

Sulfonamide Coupling:

S_(f)—S(═O)₂—Y+Q—NH₂→S_(f)—S(═O)₂—NH—Q

Reductive Amidation:

S_(f)—CHO+Q—NH₂→S_(f)—NH—Q

In these reaction schemes, the substituents S_(f) and Q can be reversedas well.

The linking group L_(n) can serve several roles. First it provides aspacing group between the metal chelator or bonding moiety, C_(h), theparamagnetic metal ion or heavy atom containing solid particle, X², andthe surfactant microsphere, X³, and the one or more of the peptides orpeptidomimetics, Q, so as to minimize the possibility that the moietiesC_(h)—X, C_(h)—X¹, X², and X³, will interfere with the interaction ofthe recognition sequences of Q with angiogenic tumor vasculaturereceptors. The necessity of incorporating a linking group in a reagentis dependent on the identity of Q, C_(h)—X, C_(h)—X¹, X², and X³. IfC_(h)—X, C_(h)—X¹, X², and X³, cannot be attached to Q withoutsubstantially diminishing its affinity for the receptors, then a linkinggroup is used. A linking group also provides a means of independentlyattaching multiple peptides and peptidomimetics, Q, to one group that isattached to C_(h)—X, C_(h)—X, X², or X³.

The linking group also provides a means of incorporating apharmacokinetic modifier into the pharmaceuticals of the presentinvention. The pharmacokinetic modifier serves to direct thebiodistibution of the injected pharmaceutical other than by theinteraction of the targeting moieties, Q, with the receptors expressedin the tumor neovasculature. A wide variety of functional groups canserve as pharmacokinetic modifiers, including, but not limited to,carbohydrates, polyalkylene glycols, peptides or other polyamino acids,and cyclodextrins. The modifiers can be used to enhance or decreasehydrophilicity and to enhance or decrease the rate of blood clearance.The modifiers can also be used to direct the route of elimination of thepharmaceuticals. Preferred pharmacokinetic modifiers are those thatresult in moderate to fast blood clearance and enhanced renal excretion.

The metal chelator or bonding moiety, C_(h), is selected to form stablecomplexes with the metal ion chosen for the particular application.Chelators or bonding moieties for diagnostic radiopharmaceuticals areselected to form stable complexes with the radioisotopes that haveimageable gamma ray or positron emissions, such as ^(99m)Tc, ⁹⁵Tc,₁₁₁In, ⁶²Cu, ⁶⁰Cu, ⁶⁴Cu, ⁶⁷Ga, ⁶⁸Ga, ⁸⁶Y.

Chelators for technetium, copper and gallium isotopes are selected fromdiaminedithiols, monoamine-monoamidedithiols, triamide-monothiols,monoamine-diamide-monothiols, diaminedioximes, and hydrazines. Thechelators are generally tetradentate with donor atoms selected fromnitrogen, oxygen and sulfur. Preferred reagents are comprised ofchelators having amine nitrogen and thiol sulfur donor atoms andhydrazine bonding units. The thiol sulfur atoms and the hydrazines maybear a protecting group which can be displaced either prior to using thereagent to synthesize a radiopharmaceutical or preferably in situ duringthe synthesis of the radiopharmaceutical.

Exemplary thiol protecting groups include those listed in Greene andWuts, “Protective Groups in Organic Synthesis” John Wiley & Sons, NewYork (1991), the disclosure of which is hereby incorporated byreference. Any thiol protecting group known in the art can be used.Examples of thiol protecting groups include, but are not limited to, thefollowing: acetamidomethyl, benzamidomethyl, 1-ethoxyethyl, benzoyl, andtriphenylmethyl.

Exemplary protecting groups for hydrazine bonding units are hydrazoneswhich can be aldehyde or ketone hydrazones having substituents selectedfrom hydrogen, alkyl, aryl and heterocycle. Particularly preferredhydrazones are described in co-pending U.S. Ser. No. 08/476,296 thedisclosure of which is herein incorporated by reference in its entirety.

The hydrazine bonding unit when bound to a metal radionuclide is termeda hydrazido, or diazenido group and serves as the point of attachment ofthe radionuclide to the remainder of the radiopharmaceutical. Adiazenido group can be either terminal (only one atom of the group isbound to the radionuclide) or chelating. In order to have a chelatingdiazenido group at least one other atom of the group must also be boundto the radionuclide. The atoms bound to the metal are termed donoratoms.

Chelators for ¹¹¹In and ⁸⁶Y are selected from cyclic and acyclicpolyaminocarboxylates such as DTPA, DOTA, DO3A, 2-benzyl-DOTA,alpha-(2-phenethyl)1,4,7,10-tetraazazcyclododecane-1-acetic-4,7,10-tris(methylacetic)acid,2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid,2-benzyl-6-methyl-DTPA, and6,6″-bis[N,N,N″,N″-tetra(carboxymethyl)aminomethyl)-4′-(3-amino-4-methoxyphenyl)-2,2′:6′,2″-terpyridine.Procedures for synthesizing these chelators that are not commerciallyavailable can be found in Brechbiel, M. and Gansow, O., J. Chem. Soc.Perkin Trans. 1992, 1, 1175; Brechbiel, M. and Gansow, O., BioconjugateChem. 1991, 2, 187; Deshpande, S., et. al., J. Nucl. Med. 1990, 31, 473;Kruper, J., U.S. Pat. No. 5,064,956, and Toner, J., U.S. Pat. No.4,859,777, the disclosures of which are hereby incorporated by referencein their entirety.

The coordination sphere of metal ion includes all the ligands or groupsbound to the metal. For a transition metal radionuclide to be stable ittypically has a coordination number (number of donor atoms) comprised ofan integer greater than or equal to 4 and less than or equal to 8; thatis there are 4 to 8 atoms bound to the metal and it is said to have acomplete coordination sphere. The requisite coordination number for astable radionuclide complex is determined by the identity of theradionuclide, its oxidation state, and the type of donor atoms. If thechelator or bonding unit does not provide all of the atoms necessary tostabilize the metal radionuclide by completing its coordination sphere,the coordination sphere is completed by donor atoms from other ligands,termed ancillary or co-ligands, which can also be either terminal orchelating.

A large number of ligands can serve as ancillary or co-ligands, thechoice of which is determined by a variety of considerations such as theease of synthesis of the radiopharmaceutical, the chemical and physicalproperties of the ancillary ligand, the rate of formation, the yield,and the number of isomeric forms of the resulting radiopharmaceuticals,the ability to administer said ancillary or co-ligand to a patientwithout adverse physiological consequences to said patient, and thecompatibility of the ligand in a lyophilized kit formulation. The chargeand lipophilicity of the ancillary ligand will effect the charge andlipophilicity of the radiopharmaceuticals. For example, the use of4,5-dihydroxy-1,3-benzene disulfonate results in radiopharmaceuticalswith an additional two anionic groups because the sulfonate groups willbe anionic under physiological conditions. The use of N-alkylsubstituted 3,4-hydroxypyridinones results in radiopharmaceuticals withvarying degrees of lipophilicity depending on the size of the alkylsubstituents.

Preferred technetium radiopharmaceuticals of the present invention arecomprised of a hydrazido or diazenido bonding unit and an ancillaryligand, A_(L1), or a bonding unit and two types of ancillary A_(L1) andA_(L2), or a tetradentate chelator comprised of two nitrogen and twosulfur atoms. Ancillary ligands A_(L1) are comprised of two or more harddonor atoms such as oxygen and amine nitrogen (sp³ hybridized). Thedonor atoms occupy at least two of the sites in the coordination sphereof the radionuclide metal; the ancillary ligand A_(L1) serves as one ofthe three ligands in the ternary ligand system. Examples of ancillaryligands A_(L1) include but are not limited to dioxygen ligands andfunctionalized aminocarboxylates. A large number of such ligands areavailable from commercial sources.

Ancillary dioxygen ligands include ligands that coordinate to the metalion through at least two oxygen donor atoms. Examples include but arenot limited to: glucoheptonate, gluconate, 2-hydroxyisobutyrate,lactate, tartrate, mannitol, glucarate, maltol, Kojic acid,2,2-bis(hydroxymethyl)propionic acid, 4,5-dihydroxy-1,3-benzenedisulfonate, or substituted or unsubstituted 1,2 or 3,4hydroxypyridinones. (The names for the ligands in these examples referto either the protonated or non-protonated forms of the ligands.)

Functionalized aminocarboxylates include ligands that have a combinationof amine nitrogen and oxygen donor atoms. Examples include but are notlimited to: iminodiacetic acid, 2,3-diaminopropionic acid,nitrilotriacetic acid, N,N′-ethylenediamine diacetic acid,N,N,N′-ethylenediamine triacetic acid, hydroxyethylethylenediaminetriacetic acid, and N,N′-ethylenediamine bis-hydroxyphenylglycine. (Thenames for the ligands in these examples refer to either the protonatedor non-protonated forms of the ligands.)

A series of functionalized aminocarboxylates are disclosed by Bridgeret. al. in U.S. Pat. No. 5,350,837, herein incorporated by reference,that result in improved rates of formation of technetium labeledhydrazino modified proteins. We have determined that certain of theseaminocarboxylates result in improved yields of the radiopharmaceuticalsof the present invention. The preferred ancillary ligands A_(L1)functionalized aminocarboxylates that are derivatives of glycine; themost preferred is tricine (tris(hydroxymethyl)methylglycine).

The most preferred technetium radiopharmaceuticals of the presentinvention are comprised of a hydrazido or diazenido bonding unit and twotypes of ancillary designated A_(L1) and A_(L2), or a diaminedithiolchelator. The second type of ancillary ligands A_(L2) are comprised ofone or more soft donor atoms selected from the group: phosphinephosphorus, arsine arsenic, imine nitrogen (sp₂ hybridized), sulfur (sp²hybridized) and carbon (sp hybridized); atoms which have p-acidcharacter. Ligands A_(L2) can be monodentate, bidentate or tridentate,the denticity is defined by the number of donor atoms in the ligand. Oneof the two donor atoms in a bidentate ligand and one of the three donoratoms in a tridentate ligand must be a soft donor atom. We havedisclosed in co-pending U.S. Ser. No. 08/415,908, and U.S. S. No.60/013,360 and Ser. No. 08/646,886, the disclosures of which are hereinincorporated by reference in their entirety, that radiopharmaceuticalscomprised of one or more ancillary or co-ligands A_(L2) are more stablecompared to radiopharmaceuticals that are not comprised of one or moreancillary ligands, A_(L2); that is, they have a minimal number ofisomeric forms, the relative ratios of which do not change significantlywith time, and that remain substantially intact upon dilution.

The ligands A_(L2) that are comprised of phosphine or arsine donor atomsare trisubstituted phosphines, trisubstituted arsines, tetrasubstituteddiphosphines and tetrasubstituted diarsines. The ligands A_(L2) that arecomprised of imine nitrogen are unsaturated or aromaticnitrogen-containing, 5 or 6-membered heterocycles. The ligands that arecomprised of sulfur (sp² hybridized) donor atoms are thiocarbonyls,comprised of the moiety C═S. The ligands comprised of carbon (sphybridized) donor atoms are isonitriles, comprised of the moiety CNR,where R is an organic radical. A large number of such ligands areavailable from commercial sources. Isonitriles can be synthesized asdescribed in European Patent 0107734 and in U.S. Pat. No. 4,988,827,herein incorporated by reference.

Preferred ancillary ligands A_(L2) are trisubstituted phosphines andunsaturated or aromatic 5 or 6 membered heterocycles. The most preferredancillary ligands A_(L2) are trisubstituted phosphines and unsaturated 5membered heterocycles.

The ancillary ligands A_(L2) may be substituted with alkyl, aryl,alkoxy, heterocycle, aralkyl, alkaryl and arylalkaryl groups and may ormay not bear functional groups comprised of heteroatoms such as oxygen,nitrogen, phosphorus or sulfur. Examples of such functional groupsinclude but are not limited to: hydroxyl, carboxyl, carboxamide, nitro,ether, ketone, amino, ammonium, sulfonate, sulfonamide, phosphonate, andphosphonamide. The functional groups may be chosen to alter thelipophilicity and water solubility of the ligands which may affect thebiological properties of the radiopharmaceuticals, such as altering thedistribution into non-target tissues, cells or fluids, and the mechanismand rate of elimination from the body.

Chelators or bonding moieties for therapeutic radiopharmaceuticals areselected to form stable complexes with the radioisotopes that have alphaparticle, beta particle, Auger or Coster-Kronig electron emissions, suchas ¹⁸⁶Re, ¹⁸⁸Re, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁰³Pd, ¹⁰⁹Pd,¹⁵⁹Gd, ¹⁴⁰La, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, ¹⁰⁵Rh,₁₁₁Ag, and ¹⁹²Ir. Chelators for rhenium, copper, palladium, platinum,iridium, rhodium, silver and gold isotopes are selected fromdiaminedithiols, monoamine-monoamidedithiols, triamide-monothiols,monoamine-diamide-monothiols, diaminedioximes, and hydrazines. Chelatorsfor yttrium, bismuth, and the lanthanide isotopes are selected fromcyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, DO3A,2-benzyl-DOTA,alpha-(2-phenethyl)1,4,7,10-tetraazacyclododecane-1-acetic-4,7,10tris(methylacetic)acid,2-benzylcyclohexyldiethylenetriaminepentaacetic acid,2-benzyl-6-methyl-DTPA, and6,6″-bis[N,N,N″,N″-tetra(carboxymethyl)aminomethyl)-4′-(3-amino-4-methoxyphenyl)-2,2′:6′,2″-terpyridine.

Chelators for magnetic resonance imaging contrast agents are selected toform stable complexes with paramagnetic metal ions, such as Gd(III),Dy(III), Fe(III), and Mn(II), are selected from cyclic and acyclicpolyaminocarboxylates such as DTPA, DOTA, DO3A, 2-benzyl-DOTA,alpha-(2-phenethyl)1,4,7,10-tetraazacyclododecane-1-acetic-4,7,10-tris(methylacetic)acid,2-benzylcyclohexyldiethylenetriaminepentaacetic acid,2-benzyl-6-methyl-DTPA, and6,6″-bis[N,N,N″,N″-tetra(carboxymethyl)aminomethyl)-4′-(3amino-4-methoxyphenyl)-2,2′:6′,2″-terpyridine.

The technetium and rhenium radiopharmaceuticals of the present inventioncomprised of a hydrazido or diazenido bonding unit can be easilyprepared by admixing a salt of a radionuclide, a reagent of the presentinvention, an ancillary ligand A_(L1), an ancillary ligand A_(L2), and areducing agent, in an aqueous solution at temperatures from 0 to 100° C.The technetium and rhenium radiopharmaceuticals of the present inventioncomprised of a tetradentate chelator having two nitrogen and two sulfuratoms can be easily prepared by admixing a salt of a radionuclide, areagent of the present invention, and a reducing agent, in an aqueoussolution at temperatures from 0 to 100° C.

When the bonding unit in the reagent of the present invention is presentas a hydrazone group, then it must first be converted to a hydrazine,which may or may not be protonated, prior to complexation with the metalradionuclide. The conversion of the hydrazone group to the hydrazine canoccur either prior to reaction with the radionuclide, in which case theradionuclide and the ancillary or co-ligand or ligands are combined notwith the reagent but with a hydrolyzed form of the reagent bearing thechelator or bonding unit, or in the presence of the radionuclide inwhich case the reagent itself is combined with the radionuclide and theancillary or co-ligand or ligands. In the latter case, the pH of thereaction mixture must be neutral or acidic.

Alternatively, the radiopharmaceuticals of the present inventioncomprised of a hydrazido or diazenido bonding unit can be prepared byfirst admixing a salt of a radionuclide, an ancillary ligand A_(L1), anda reducing agent in an aqueous solution at temperatures from 0 to 100°C. to form an intermediate radionuclide complex with the ancillaryligand A_(L1) then adding a reagent of the present invention and anancillary ligand A_(L2) and reacting further at temperatures from 0 to100° C.

Alternatively, the radiopharmaceuticals of the present inventioncomprised of a hydrazido or diazenido bonding unit can be prepared byfirst admixing a salt of a radionuclide, an ancillary ligand A_(L1), areagent of the present invention, and a reducing agent in an aqueoussolution at temperatures from 0 to 100° C. to form an intermediateradionuclide complex, and then adding an ancillary ligand A_(L2) andreacting further at temperatures from 0 to 100° C.

The technetium and rhenium radionuclides are preferably in the chemicalform of pertechnetate or perrhenate and a pharmaceutically acceptablecation. The pertechnetate salt form is preferably sodium pertechnetatesuch as obtained from commercial Tc-99m generators. The amount ofpertechnetate used to prepare the radiopharmaceuticals of the presentinvention can range from 0.1 mCi to 1 Ci, or more preferably from 1 to200 mCi.

The amount of the reagent of the present invention used to prepare thetechnetium and rhenium radiopharmaceuticals of the present invention canrange from 0.01 μg to 10 mg, or more preferably from 0.5 μg to 200 μg.The amount used will be dictated by the amounts of the other reactantsand the identity of the radiopharmaceuticals of the present invention tobe prepared.

The amounts of the ancillary ligands A_(L1) used can range from 0.1 mgto 1 g, or more preferably from 1 mg to 100 mg. The exact amount for aparticular radiopharmaceutical is a function of identity of theradiopharmaceuticals of the present invention to be prepared, theprocedure used and the amounts and identities of the other reactants.Too large an amount of A_(L1) will result in the formation ofby-products comprised of technetium labeled A_(L1) without abiologically active molecule or by-products comprised of technetiumlabeled biologically active molecules with the ancillary ligand A_(L1)but without the ancillary ligand A_(L2). Too small an amount of A_(L1)will result in other by-products such as technetium labeled biologicallyactive molecules with the ancillary ligand A_(L2) but without theancillary ligand A_(L1), or reduced hydrolyzed technetium, or technetiumcolloid.

The amounts of the ancillary ligands A_(L2) used can range from 0.001 mgto 1 g, or more preferably from 0.01 mg to 10 mg. The exact amount for aparticular radiopharmaceutical is a function of the identity of theradiopharmaceuticals of the present invention to be prepared, theprocedure used and the amounts and identities of the other reactants.Too large an amount of A_(L2) will result in the formation ofby-products comprised of technetium labeled A_(L2) without abiologically active molecule or by-products comprised of technetiumlabeled biologically active molecules with the ancillary ligand A_(L2)but without the ancillary ligand A_(L1). If the reagent bears one ormore substituents that are comprised of a soft donor atom, as definedabove, at least a ten-fold molar excess of the ancillary ligand A_(L2)to the reagent of formula 2 is required to prevent the substituent frominterfering with the coordination of the ancillary ligand A_(L2) to themetal radionuclide.

Suitable reducing agents for the synthesis of the radiopharmaceuticalsof the present invention include stannous salts, dithionite or bisulfitesalts, borohydride salts, and formamidinesulfinic acid, wherein thesalts are of any pharmaceutically acceptable form. The preferredreducing agent is a stannous salt. The amount of a reducing agent usedcan range from 0.001 mg to 10 mg, or more preferably from 0.005 mg to 1mg.

The specific structure of a radiopharmaceutical of the present inventioncomprised of a hydrazido or diazenido bonding unit will depend on theidentity of the reagent of the present invention used, the identity ofany ancillary ligand A_(L1), the identity of any ancillary ligandA_(L2), and the identity of the radionuclide. Radiopharmaceuticalscomprised of a hydrazido or diazenido bonding unit synthesized usingconcentrations of reagents of <100 μg/mL, will be comprised of onehydrazido or diazenido group. Those synthesized using >1 mg/mLconcentrations will be comprised of two hydrazido or diazenido groupsfrom two reagent molecules. For most applications, only a limited amountof the biologically active molecule can be injected and not result inundesired side-effects, such as chemical toxicity, interference with abiological process or an altered biodistribution of theradiopharmaceutical. Therefore, the radiopharmaceuticals which requirehigher concentrations of the reagents comprised in part of thebiologically active molecule, will have to be diluted or purified aftersynthesis to avoid such side-effects.

The identities and amounts used of the ancillary ligands A_(L1) andA_(L2) will determine the values of the variables y and z. The values ofy and z can independently be an integer from 1 to 2. In combination, thevalues of y and z will result in a technetium coordination sphere thatis made up of at least five and no more than seven donor atoms. Formonodentate ancillary ligands A_(L2), z can be an integer from 1 to 2;for bidentate or tridentate ancillary ligands A_(L2), z is 1. Thepreferred combination for monodentate ligands is y equal to 1 or 2 and zequal to 1. The preferred combination for bidentate or tridentateligands is y equal to 1 and z equal to 1.

The indium, copper, gallium, silver, palladium, rhodium, gold, platinum,bismuth, yttrium and lanthanide radiopharmaceuticals of the presentinvention can be easily prepared by admixing a salt of a radionuclideand a reagent of the present invention, in an aqueous solution attemperatures from 0 to 100° C. These radionuclides are typicallyobtained as a dilute aqueous solution in a mineral acid, such ashydrochloric, nitric or sulfuric acid. The radionuclides are combinedwith from one to about one thousand equivalents of the reagents of thepresent invention dissolved in aqueous solution. A buffer is typicallyused to maintain the pH of the reaction mixture between 3 and 10.

The gadolinium, dysprosium, iron and manganese metallopharmaceuticals ofthe present invention can be easily prepared by admixing a salt of theparamagnetic metal ion and a reagent of the present invention, in anaqueous solution at temperatures from 0 to 100° C. These paramagneticmetal ions are typically obtained as a dilute aqueous solution in amineral acid, such as hydrochloric, nitric or sulfuric acid. Theparamagnetic metal ions are combined with from one to about one thousandequivalents of the reagents of the present invention dissolved inaqueous solution. A buffer is typically used to maintain the pH of thereaction mixture between 3 and 10.

The total time of preparation will vary depending on the identity of themetal ion, the identities and amounts of the reactants and the procedureused for the preparation. The preparations may be complete, resultingin >80% yield of the radiopharmaceutical, in 1 minute or may requiremore time. If higher purity metallopharmaceuticals are needed ordesired, the products can be purified by any of a number of techniqueswell known to those skilled in the art such as liquid chromatography,solid phase extraction, solvent extraction, dialysis or ultrafiltration.

Buffers useful in the preparation of metallopharmaceuticals and indiagnostic kits useful for the preparation of said radiopharmaceuticalsinclude but are not limited to phosphate, citrate, sulfosalicylate, andacetate. A more complete list can be found in the United StatesPharmacopeia.

Lyophilization aids useful in the preparation of diagnostic kits usefulfor the preparation of radiopharmaceuticals include but are not limitedto mannitol, lactose, sorbitol, dextran, Ficoll, andpolyvinylpyrrolidine (PVP).

Stabilization aids useful in the preparation of metallopharmaceuticalsand in diagnostic kits useful for the preparation ofradiopharmaceuticals include but are not limited to ascorbic acid,cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite,gentisic acid, and inositol.

Solubilization aids useful in the preparation of metallopharmaceuticalsand in diagnostic kits useful for the preparation ofradiopharmaceuticals include but are not limited to ethanol, glycerin,polyethylene glycol, propylene glycol, polyoxyethylene sorbitanmonooleate, sorbitan monoloeate, polysorbates,poly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymers(Pluronics) and lecithin. Preferred solubilizing aids are polyethyleneglycol, and Pluronics.

Bacteriostats useful in the preparation of metallopharmaceuticals and indiagnostic kits useful for the preparation of radiopharmaceuticalsinclude but are not limited to benzyl alcohol, benzalkonium chloride,chlorbutanol, and methyl, propyl or butyl paraben.

A component in a diagnostic kit can also serve more than one function. Areducing agent can also serve as a stabilization aid, a buffer can alsoserve as a transfer ligand, a lyophilization aid can also serve as atransfer, ancillary or co-ligand and so forth.

The diagnostic radiopharmaceuticals are administered by intravenousinjection, usually in saline solution, at a dose of 1 to 100 mCi per 70kg body weight, or preferably at a dose of 5 to 50 mCi. Imaging isperformed using known procedures.

The therapeutic radiopharmaceuticals are administered by intravenousinjection, usually in saline solution, at a dose of 0.1 to 100 mCi per70 kg body weight, or preferably at a dose of 0.5 to 5 mCi per 70 kgbody weight.

The magnetic resonance imaging contrast agents of the present inventionmay be used in a similar manner as other MRI agents as described in U.S.Pat. Nos. 5,155,215; 5,087,440; Margerstadt et al., Magn. Reson. Med.,1986, 3, 808; Runge et al., Radiology, 1988, 166, 835; and Bousquet etal., Radiology, 1988, 166, 693. Generally, sterile aqueous solutions ofthe contrast agents are administered to a patient intravenously indosages ranging from 0.01 to 1.0 mmoles per kg body weight.

For use as X-ray contrast agents, the compositions of the presentinvention should generally have a heavy atom concentration of 1 mM to 5M, preferably 0.1 M to 2 M. Dosages, administered by intravenousinjection, will typically range from 0.5 mmol/kg to 1.5 mmol/kg,preferably 0.8 mmol/kg to 1.2 mmol/kg. Imaging is performed using knowntechniques, preferably X-ray computed tomography.

The ultrasound contrast agents of the present invention are administeredby intravenous injection in an amount of 10 to 30 μL of the echogenicgas per kg body weight or by infusion at a rate of approximately 3μL/kg/min. Imaging is performed using known techniques of sonography.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Representative materials and methods that may be used in preparing thecompounds of the invention are described further below.

Manual solid phase peptide synthesis was performed in 25 mLpolypropylene filtration tubes purchased from BioRad Inc., or in 60 mLhour-glass reaction vessels purchased from Peptides International. Oximeresin (substitution level=0.96 mmol/g) was prepared according topublished procedure (DeGrado and Kaiser, J. Org. Chem. 1980, 45, 1295),or was purchased from Novabiochem (substitution level=0.62 mmol/g). Allchemicals and solvents (reagent grade) were used as supplied from thevendors cited without further purification. t-Butyloxycarbonyl (Boc)amino acids and other starting amino acids may be obtained commerciallyfrom Bachem Inc., Bachem Biosciences Inc. (Philadelphia, Pa.), AdvancedChemTech (Louisville, Ky.), Peninsula Laboratories (Belmont, Calif.), orSigma (St. Louis, Mo.).2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU) and TBTU were purchased from Advanced ChemTech.N-methylmorpholine (NMM), m-cresol, D-2-aminobutyric acid (Abu),trimethylacetylchloride, diisopropylethylamine (DIEA), 1,2,4-triazole,stannous chloride dihydrate, and tris(3-sulfonatophenyl)phosphinetrisodium salt (TPPTS) were purchased from Aldrich Chemical Company.Bis(3-sulfonatophenyl)phenylphosphine disodium salt (TPPDS) was preparedby the published procedure (Kuntz, E., U.S. Pat. No. 4,248,802).(3-Sulfonatophenyl)diphenylphosphine monosodium salt (TPPMS) waspurchased from TCI America, Inc. Tricine was obtained from ResearchOrganics, Inc. Technetium-99m-pertechnetate (^(99m)TcO₄ ⁻) was obtainedfrom a DuPont Pharma ⁹⁹Mo/^(99m)Tc Technelite® generator.In-111-chloride (Indichlor®) was obtained from Amersham Medi-Physics,Inc. Sm-153-chloride and Lutetium-177-chloride were obtained from theUniversity of Missouri Research Reactor (MURR). Yttrium-90 chloride wasobtained from the Pacific Northwest Research Laboratories.Dimethylformamide (DMF), ethyl acetate, chloroform (CHCl₃), methanol(MeOH), pyridine and hydrochloric acid (HCl) were obtained from Baker.Acetonitrile, dichloromethane (DCM), acetic acid (HOAc), trifluoroaceticacid (TFA), ethyl ether, triethylamine, acetone, and magnesium sulfatewere commercially obtained. Absolute ethanol was obtained from QuantumChemical Corporation.

General Procedure for Solid Phase Peptide Synthesis Using Boc-Chemistryon the Oxime Resin for the Preparation of Cyclic Peptides

The appropriately protected cyclic peptides, described in the Examples,were prepared by manual solid phase peptide synthesis using Boc-teabagchemistry (Houghton, 1985) on a p-nitrobenzophenone oxime solid support(DeGrado, 1982, Scarr and Findeis, 1990). The 5.0 cm×5.0 cm teabags weremade from 0.75 mm mesh polypropylene filters (Spectra Filters) andfilled with 0.5 g (or 1 g) of the oxime resin. The coupling anddeprotection steps were carried out in a polypropylene reactor using atable-top shaker for agitation. Synthesis of the protectedpentapeptide-resin intermediate was achieved by first couplingBoc-Gly-OH to the oxime resin (substitution 0.69 mmol/g or 0.95 mmol/g).Attachment of Boc-Gly-OH onto the oxime resin was achieved by using fiveequivalents each of the amino acid, HBTU and diisopropylethylamine(DIPEA) in DMF. Coupling of the first amino acid generally occurred over2-3 days. After thorough washing, substitution levels were determinedusing the picric acid assay (Stewart and Martin). Unreacted oxime groupson the resin were then capped with a solution of DIPEA andtrimethylacetyl chloride in DMF. The boc-group was deprotected using 50%or 25% TFA in DCM (30 min). Coupling of the other protected boc-aminoacids were performed in a similar manner by overnight shaking (1-2days), and the coupling yields for each newly added amino acid wasdetermined using the picric acid assay.

General Procedure for Solid Phase Peptide Synthesis Using Fmoc-Chemistryon the HMPB-BHA Resin for the Preparation of Cyclic Peptides

The appropriately protected linear peptide precursors to the cyclicpeptides, described in the Examples, were also prepared by automatedsolid phase peptide synthesis using Fmoc chemistry on an AdvancedChemTech Model 90 Synthesizer and using HMPB-BHA resin as the solidsupport. Synthesis of the protected pentapeptide-resin intermediates wasachieved by coupling (for 3 h) the Fmoc-amino acids sequentially to thecommercially available (Novabiochem) Fmoc-Gly-HMPB-BHA resin (usually 2g, substitution 0.47 to 0.60 mmol/g) by using three to five equivalentseach of the amino acid, HBTU, HOBt and diisopropylethylamine (DIPEA) inDMF. The Fmoc-group was deprotected using 20% piperidine in DMF (30min). The peptides were cleaved from the HMPB-BHA resin using a solutionof 1% TFA/DCM and collecting the peptide solutions in a solution ofpyridine in methanol (1:10). The linear protected peptides were isolatedby removing the solvents and reagents in vacuo and triturating the cruderesidue in diethyl ether.

The syntheses of several amino acids that are not commercially availableare described in the following procedures.

Synthesis of Tfa-amino Acids

Boc-HomoLys(Tfa)-OH and Boc-Cys(2-N-Tfa-aminoethyl)-OH are prepared viathe reaction of Boc-HomoLys-OH and Boc-Cys(2-aminoethyl)-OH,respectively, with ethyl thioltrifluoroacetate in Aq. NaOH, and purifiedby recrystallization from ethanol.

Synthesis of Boc-Orn(d-N-Benzylcarbamoyl)

To a solution of Boc-Orn (1 mmol) in DMF (30 mL) is addedbenzylisocyanate (2.2 mmol), and diisopropylamine (3 mmol). The reactionmixture is then stirred overnight at room temperature. The volatiles areremoved in vacuo and the crude material is purified by columnchromatography to obtain the desired product.

Synthesis of Boc-Orn(d-N-1-Tos-2-Imidazolinyl)

A solution of Boc-Orn-OH (10 mmol), 1-tosyl-2-methylthio-2-imidazoline(12 mmol, (which in turn is prepared from the reaction of thecommercially available 2-methylthio-2-imidazoline hydriodide andp-toluenesulfonic anhydride in methylene chloride (0° C. to RT) in thepresence of triethylamine)), and diisopropylethylamine (12 mmol) isstirred at reflux, overnight. The volatiles are removed and the desiredproduct isolated by chromatography.

Synthesis of Dap(b-(1-Tos-2-benzimidazolylacetyl))

To a solution of 1-Tos-2-benzimidazolylacetic acid (10 mmol, preparedusing tosyl chloride and standard reported conditions) andN-methylmorpholine (10 mmol) in anhydrous DMF is added isobutylchloroformate (10 mmol). After stirring at ice bath temperature for 5-10min., Boc-Orn-OH (10 mmol) and N-methylmorpholine (20 mmol) in anhydrousDMF is added in one portion. The reaction mixture is stirred overnightat room temperature, the volatiles removed in vacuo, and the product isisolated by chromatography. (Alternatively, Boc-Orn-OMe is used and theproduct isolated is treated with aqueous LiOH to obtain the acid.)

The analytical HPLC methods utilized are described below:

HPLC Method 1

Instrument: HP1050

Column: Vydac C18(4.6×250 mm)

Detector: Diode array detector 220 nm/500 ref

Flow Rate: 1.0 mL/min.

Column Temp: 50° C.

Sample Size: 15 uL

Mobile Phase:

A: 0.1% TFA in water

B: 0.1% TFA in ACN/Water (9:1)

Time (min) % A % B Gradient A: 0 80 20 20 0 100 30 0 100 31 80 20Gradient B: 0 98 2 16 63.2 36.8 18 0 100 28 0 100 30 98 2

Example 1 Synthesis ofcyclo{Arg-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Part A: Preparation of cyclo{Arg(Tos)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Tyr(N-Cbz-aminopropyl)-Val-Arg(Tos)-Gly-Oxime resin wasremoved using standard deprotection (25% TFA in CH₂Cl₂). After eightwashes with DCM, the resin was treated with 10% DIEA/DCM (2×10 min.).The resin was subsequently washed with DCM (×5) and dried under highvacuum. The resin (1.7474 g, 0.55 mmol/g) was then suspended indimethylformamide (15 mL). Glacial acetic acid (55.0 μL, 0.961 mmol) wasadded, and the reaction mixture was heated at 50° C. for 72 h. The resinwas filtered, and washed with DMF (2×10 mL). The filtrate wasconcentrated to an oil under high vacuum. The resulting oil wastriturated with ethyl acetate. The solid thus obtained was filtered,washed with ethyl acetate, and dried under high vacuum to give 444.4 mgof the desired product. ESMS: Calcd. for C₅₁H₆₃N₉O₁₂S, 1025.43; Found,1026.6 [M+H]+1. Analytical HPLC, Method 1A, R_(t)=14.366 min,Purity=75%.

Part B: Preparation ofcyclo{Arg-Gly-Asp-D-Tyr(3-aminopropyl)-Val}Trifluoroacetic acid salt

Cyclo{Arg(Tos)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val} (0.150 g,0.146 mmol) was dissolved in trifluoroacetic acid (0.6 mL) and cooled to−10° C. Trifluoromethanesulfonic acid (0.5 mL) was added dropwise,maintaining the temperature at −10° C. Anisole (0.1 mL) was added andthe reaction mixture was stirred at −10° C. for 3 h. Diethyl ether wasadded, the reaction mixture cooled to −35° C. and then stirred for 30min. The reaction mixture was cooled further to −50° C. and stirred for30 min. The crude product obtained was filtered, washed with diethylether, dried under high vacuum, and purified by preparative HPLC Method1, to give 29.7 mg (23%) of the desired product as a lyophilized solid.ESMS: Calcd. for C₂₉H₄₅N₉O₈, 647.34; Found, 648.5 [M+H]+1. AnalyticalHPLC, Method 1B, R_(t)=10.432 min, Purity=91%.

Preparative HPLC Method 1

Instrument: Rainin Rabbit; Dynamax software

Column: Vydac C-18 (21.2 mm×25 cm)

Detector: Knauer VWM

Flow Rate: 15 ml/min

Column Temp: RT

Mobile Phase:

A: 0.1% TFA in H₂O

B: 0.1%TFA in ACN/H₂O (9:1)

Gradient: Time (min) % A % B 0 98 2 16 63.2 36.8 18 0 100 28 0 100 30 982

Part C. Preparation ofcyclo{Arg-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Cyclo{Arg-Gly-Asp-D-Tyr(3-aminopropyl)-Val}trifluoroacetic acid salt(0.020 g, 0.0228 mmol) was dissolved in DMF (1 mL). Triethylamine (9.5μL, 0.0648 mmol) was added, and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0121 g, 0.0274 mmol) was added. The reactionmixture was stirred for 7 days, and then concentrated to an oil underhigh vacuum. The oil was purified by preparative HPLC Method 1 to give8.9 mg (37%) of the title product as a lyophilized solid (TFA salt).HRMS: Calcd. for C₄₂H₅₄N₁₂O₁₂S+H, 951.3783; Found, 951.3767. AnalyticalHPLC, Method 1B, R_(t)=14.317 min, Purity=95%.

Example 2 Synthesis ofcyclo{Arg-Gly-Asp-D-Tyr((N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-18-amino-14-aza-4,7,10-oxy-15-oxo-octadecoyl)-3-aminopropyl)-Val}

Part A: Preparation of3-(N-(3-(2-(2-(3-((tert-butoxy)-carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)-propanoicacid

N-(3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)(tert-butoxy)formamide(1.5 g, 4.68 mmol) was added to DMF (15 mL). To this solution pyridine(15 mL), succinic anhydride (0.47 g, 4.68 mmol) were added, followed bydimethylaminopyridine (62 mL, 0.468 μmol). The reaction mixture wasstirred overnight at 100° C. The mixture was concentrated under highvacuum and the residue was brought up in water, acidified to pH 2.5 with1N HCl, and extracted with ethyl acetate (3×). The combined organicextracts were dried over MgSO₄ and filtered. The filtrate wasconcentrated in vacuo to provide 1.24 g of an oil product (63%). Thedesired product was used without further purification. ¹H NMR (CDCl₃)3.67-3.45 (m, 11H), 3.41-3.28 (m, 2H), 3.21-3.09 (m, 2H), 2.95-2.82 (m,2H), 2.80-2.35 (m, 3H), 1.81-1.68 (m, 4H), 1.50-1.35 (s, 9H); ESMS:Calculated for C₁₉H₃₆N₂O₈, 420.2471 Found 419.3 [M−H]−1.

Part B: Preparation of3-(N-(3-(2-(2-(3-((tert-butoxy)-carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoicacid succinimide ester

To a solution of3-(N-(3-(2-(2-(3-((tert-butoxy)-carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)-propanoicacid (1.12 g, 2.66 mmol), N-hydroxysuccinimide (0.40 g, 3.46 mmol), andN,N-dimethylformamide (40 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodimide (0.67 g, 3.46 mmol). Thereaction mixture was stirred at room temperature for 48 h. The mixturewas concentrated under high vacuum and the residue was brought up in0.1N HCl and extracted with ethyl acetate (3×). The combined organicextracts were washed with water (2×) then saturated sodium chloride,dried over MgSO₄, and filtered. The filtrate was cocnentrated in vacuoto give 1.0 g of the product as an oil (73%). The desired product wasused without further purification. ESMS: Calculated for C₂₃H₃₉N₃O₁₀,517.2635 Found 518.2 [M+H]+1.

Part C. Preparation ofcyclo{Arg-Gly-Asp-D-Tyr(3-(3-(N-(3-(2-(2-(3-((tert-butoxy)-carbonylamino)propoxy)ethoxy)-ethoxy)propyl)carbamoyl)-propanamido)propyl)-Val}

Cyclo{Arg-Gly-Asp-D-Tyr(3-aminopropyl)-Val}. TFA salt (0.040 g, 0.0457mmol) was dissolved in DMF (2 mL). Triethylamine (19.1 μL, 0.137 mmol)was added and after stirring for 5 minutes3-(N-(3-(2-(2-(3-((tert-butoxy)-carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoicacid succinimide ester (0.0284 g, 0.0548 mmol) was added. The reactionmixture was stirred under N₂ for 48 h and then concentrated to an oilunder high vacuum. The oil was triturated with ethyl acetate, theproduct filtered, washed with ethyl acetate, and dried under highvacuum. The crude product was purified by Preparative HPLC Method 1 togive 7.4 mg (14%) of the desired product as a lyophilized solid. ESMS:Calcd. for C₄₈H₇₉N₁₁O₁₅, 1049.58; Found, 1050.5 [M+H]+1. AnalyticalHPLC, Method 1B, R_(t)=20.417 min, Purity=100%.

Part D. Preparation ofcyclo{Arg-Gly-Asp-D-Tyr(3-(3-(N-(3-(2-(2-(3-(amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)-propanamido)propyl)-Val}

Cyclo{Arg-Gly-Asp-D-Tyr(3-(3-(N-(3-(2-(2-(3-((tert-butoxy)-carbonylamino)propoxy)ethoxy)ethoxy)propyl)-carbamoyl)-propanamido)propyl)-Val}(6.0 mg, 0.00515 mmol) was dissolved in methylene chloride (1 mL) andtrifluoroacetic acid (1 mL) was added. The solution stirred for 2 h andthen concentrated to an oil under high vacuum. The oil was trituratedwith diethyl ether, the product filtered, washed with diethyl ether, anddried under high vacuum to give 6.0 mg (98%) of the desired product.ESMS: Calcd. for C₄₃H₇₁N₁₁O₁₃, 949.52; Found, 950.6 [M+H]+1. AnalyticalHPLC, Method 1B, R_(t)=14.821 min, Purity=73%.

Part E. Preparation ofcyclo{Arg-Gly-Asp-D-Tyr((N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-18-amino-14-aza-4,7,10-oxy-15-oxo-octadecoyl)-3-aminopropyl)-Val}

Cyclo{Arg-Gly-Asp-D-Tyr(3-(3-(N-(3-(2-(2-(3-(amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)-propanamido)propyl)-Val}(5.0 mg, 0.00424 mmol) was dissolved in dimethylformamide (1 mL).Triethylamine (1.8 μL, 0.0127 mmol) was added, and after stirring for 5min2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]-carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid, monosodium salt (2.2 mg, 0.00509 mmol) was added. The reactionmixture was stirred for 24 h and then concentrated to an oil under highvacuum. The oil was purified by preparative HPLC Method 1 to give 2.2 mg(38%) of the desired product as a lyophilized solid (TFA salt). ESMS:Calcd. for C₅₆H₈₀N₁₄O₁₇S, 1252.6; Found, 1253.7 (M+H⁺). Analytical HPLC,Method 1B, R_(t)==17.328 min, Purity=100%.

Example 3 Synthesis of[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp})-cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp}

Part A. Preparation ofBoc-Glu(cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp})-cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp}

Cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp} (0.040 g, 0.0457 mmol) wasdissolved in dimethylformamide (2 mL). Triethylamine (19.1 μL, 0.137mmol) was added and the reaction mixture was stirred for 5 minutes.Boc-Glu(OSu)-OSu (0.0101 g, 0.0.229 mmol) was added and the reactionmixture was stirred under N₂ for 18 h. The reaction mixture was thenconcentrated to an oil under high vacuum. The oil was triturated withethyl acetate. The product was filtered, washed with ethyl acetate, anddried under high vacuum to give 38.0 mg (55%) of the desired product.ESMS: Calcd. for C₆₈H₁₀₃N₁₉O₂₀, 1505.76; Found, 1504.9 [M−H]−1.Analytical HPLC, Method 1B, R_(t)=19.797 min, Purity=73%.

Part B. Preparation ofGlu(cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp})-cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp}.TFAsalt

Boc-Glu(cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp})-cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp}(0.035 g, 0.0232 mmol) was dissolved in methylene chloride (1 mL).Trifluoroacetic acid (1 mL) was added, and the reaction mixture wasstirred for 2 h, concentrated to an oil under high vacuum and trituratedwith ether. The product obtained was filtered, washed with diethylether, and dried under high vacuum to give 30.7 mg (76%) of the desiredproduct. ESMS: Calcd. for C₆₃H₉₅N₁₉O₁₈, 1405.71; Found, 1404.7 [M−H]−1.Analytical HPLC, Method 1B, R_(t)=15.907 min, Purity=77%.

Part C. Preparation of[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp})-cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp}

To a solution ofGlu(cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp})-cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp}(0.025 g, 0.0143 mmol) in dimethylformamide (2 mL) was addedtriethylamine (6.0 μL, 0.0429 mmol) and the reaction mixture was stirredfor 5 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0076 g, 0.0172 mmol) was added, and thereaction mixture was stirred for 5 days, then concentrated to an oilunder high vacuum. The oil was purified by Preparative HPLC Method 1 togive 12.0 mg (43%) of the desired product as a lyophilized solid. ESMS:Calcd. for C₇₆H₁₀₄N₂₂O₂₂S, 1708.7; Found, 1710.1 (M+H⁺). AnalyticalHPLC, Method 1B, R_(t)=17.218 min, Purity=94%.

Example 4 Synthesis ofcyclo(Arg-Gly-Asp-D-Tyr-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Part A. Preparation of cyclo{Arg(Tos)-Gly-Asp(OBzl)-D-Tyr(Bzl)-Lys(Cbz)}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Tyr(Bzl)-Lys(Z)-Arg(Tos)-Gly-oxime resin was removedusing standard deprotection (25% TFA in CH₂Cl₂). After eight washes withDCM, the resin was treated with 10% DIEA/DCM (2×10 min.). The resin wassubsequently washed with DCM (×5) and dried under high vacuum. The resin(1.8711 g, 0.44 mmol/g) was then suspended in DMF (15 mL). Glacialacetic acid (47.1 μL, 0.823 mmol) was added, and the reaction was heatedat 60° C. for 72 h. The resin was filtered, and washed with DMF (2×10mL). The filtrate was concentrated to an oil under high vacuum. Theresulting oil was triturated with ethyl acetate. The solid thus obtainedwas filtered, washed with ethyl acetate, and dried under high vacuum togive 653.7 mg of the desired product. ESMS: Calcd. for C₅₆H₆₅N₉O₁₂S,1087.45; Found, 1088.7 [M+H]+1. Analytical HPLC, Method 1A, R_(t)=17.559min, Purity=82%.

Part B. Preparation of cyclo{Arg-Gly-Asp-D-Tyr-Lys}

Cyclo{Arg(Tos)-Gly-Asp(OBzl)-D-Tyr(Bzl)-Lys(Cbz)} (0.200 g, 0.184 mmol)was dissolved in trifluoroacetic acid (0.6 mL) and cooled to −10° C.Trifluoromethanesulfonic acid (0.5 mL) was added dropwise, maintainingthe temperature at −10° C. Anisole (0.1 mL) was added and the reactionmixture was stirred at −10° C. for 3 h. Diethyl ether was added, thereaction was cooled to −50° C., and stirred for 1 h. The crude productwas filtered, washed with diethyl ether, and dried under high vacuum.The crude product was purified by Preparative HPLC Method 1, to give15.2 mg (10%) of the desired product as a lyophilized solid. HRMS:Calcd. for C₂₇H₄₁N₉O₈+H, 620.3156; Found, 620.3145. Analytical HPLC,Method 1B, R_(t)=8.179 min, Purity=100%.

Part C. Preparation ofcyclo{Arg-Gly-Asp-D-Tyr-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Cyclo{Arg-Gly-Asp-D-Tyr-Lys}TFA salt (0.010 g, 0.0118 mmol) wasdissolved in DMF (1 mL). Triethylamine (5.0 μL, 0.0354 mmol) was added,and after stirring for 5 min2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonicacid, monosodium salt (0.0062 g, 0.0142 mmol) was added. The reactionmixture was stirred for 20 h and then concentrated to an oil under highvacuum. The oil was purified by Preparative HPLC Method 1 to give 6.2 mg(46%) of the desired product as a lyophilized solid. HRMS: Calcd. forC₄₀H₅₀N₁₂O₁₂S+H, 923.3470; Found, 923.3486. Analytical HPLC, Method 1B,R_(t)=11.954 min, Purity=100%.

Example 5 Synthesis ofcyclo{Arg-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Part A. Preparation of cyclo{Arg(Tos)-Gly-Asp(OBzl)-D-Phe-Lys(Cbz)}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Phe-Lys(Z)-Arg(Tos)-Gly-Oxime resin was removed usingstandard deprotection (25% TFA in CH₂Cl₂). After eight washes with DCM,the resin was treated with 10% DIEA/DCM (2×10 min.). The resin wassubsequently washed with DCM (×5) and dried under high vacuum. The resin(1.7053 g, 0.44 mmol/g) was then suspended in dimethylformamide (15 mL).Glacial acetic acid (43.0 μL, 0.750 mmol) was added, and the reactionwas heated to 60° C. for 72 h. The resin was filtered, and washed withDMF (2×10 mL). The filtrate was concentrated to an oil under highvacuum. The resulting oil was triturated with ethyl acetate. The solidthus obtained was filtered, washed with ethyl acetate, and dried underhigh vacuum to give 510.3 mg of the desired product. ESMS: Calcd. forC₄₉H₅₉N₉O₁₁S, 981.40; Found, 982.6 [M+H]+1. Analytical HPLC, Method 1A,R_(t)=15.574 min, Purity=89%.

Part B. Preparation of cyclo{Arg-Gly-Asp-D-Phe-Lys}

Cyclo{Arg(Tos)-Gly-Asp(OBzl)-D-Phe-Lys(Cbz)} (0.200 g, 0.204 mmol) wasdissolved in trifluoracetic acid (0.6 mL) and cooled to −10° C.Trifluoromethanesulfonic acid (0.5 mL) was added dropwise, maintainingthe temperature at −10° C. Anisole (0.1 mL) was added and the reactionwas stirred at −10° C. for 3 h. Diethyl ether was added, the reactionwas cooled to −50° C., and stirred for 1 h. The crude product wasfiltered, washed with diethyl ether, dried under high vacuum andpurified by Preparative HPLC Method 1, to give 121.1 mg (71%) of thedesired product as a lyophilized solid. HRMS: Calcd. for C₂₇H₄₁N₉O₇+H,604.3207; Found, 604.3206. Analytical HPLC, Method 1B, R_(t)=11.197 min,Purity=100%.

Part C. Preparation ofcyclo{Arg-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Cyclo{Arg-Gly-Asp-D-Phe-Lys}TFA salt (0.040 g, 0.0481 mmol) wasdissolved in DMF (2 mL). Triethylamine (20.1 μL, 0.144 mmol) was added,and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonicacid, monosodium salt (0.0254 g, 0.0577 mmol) was added. The reactionmixture was stirred for 20 h and then concentrated to an oil under highvacuum. The oil was purified by Preparative HPLC Method 1 to give 38.2mg (78%) of the desired product as a lyophilized solid. HRMS: Calcd. forC₄₀H₅₀N₁₂O₁₁S+H, 907.3521; Found, 907.3534. Analytical HPLC, Method 1B,R_(t)=14.122 min, Purity=91%.

Example 6 Synthesis of[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}

Part A. Preparation of Boc-Glu(OSu)-OSu

To a solution of Boc-Glu-OH (8.0 g, 32.25 mmol), N-hydroxysuccinimide(8.94 g, 77.64 mmol), and DMF (120 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodimide (14.88 g, 77.64 mmol). Thereaction mixture was stirred at room temperature for 48 h. The mixturewas concentrated under high vacuum and the residue was brought up in 0.1N HCl and extracted with ethyl acetate (3×). The combined organicextracts were washed with water, saturated sodium bicarbonate and thensaturated sodium chloride, dried over MgSO₄, and filtered. The filtratewas concentrated in vacuo and purified via reverse-phase HPLC (Vydac C18column, 18 to 90% acetonitrile gradient containing 0.1% TFA, R_(t)=9.413min) to afford 8.5 g (60%) of the desired product as a white powder. ¹HNMR (CDCl₃): 2.98-2.70 (m, 11H), 2.65-2.25 (m, 2H), 1.55-1.40 (s, 9H);ESMS: Calculated for C₁₈H₂₃N₃O₁₀, 441.1383 Found 459.2 [M+NH₄]+1.

Part B. Preparation ofBoc-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}

To a solution of cyclo(Lys-Arg-Gly-Asp-D-Phe) (0.050 g, 0.0601 mmol) indimethylformamide (2 mL) was added triethylamine (25.1 μL, 0.183 mmol).After stirring for 5 minutes Boc-Glu(OSu)-OSu (0.0133 g, 0.0301 mmol)was added. The reaction mixture was stirred under N₂ for 20 h, thenconcentrated to an oil under high vacuum and triturated with ethylacetate. The product thus obtained was filtered, washed with ethylacetate, and dried under high vacuum to give 43.7 mg (44%) of thedesired product. ESMS: Calcd. for C₆₄H₉₅N₁₉O₁₈, 1417.71; Found, 1418.8[M+H]+1. Analytical HPLC, Method 1B, R_(t)=19.524 min, Purity=73%.

Part C. Preparation ofGlu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}TFA salt

To a solution ofBoc-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}(0.040 g, 0.0243 mmol) in methylene chloride (1 mL) was addedtrifluoroacetic acid (1 mL). The reaction mixture was stirred for 2 h,concentrated to an oil under high vacuum and triturated with diethylether. The product was filtered, washed with diethyl ether, and driedunder high vacuum to give 39.9 mg (100%) of the desired product. ESMS:Calcd. for C₅₉H₈₇N₁₉O₁₆, 1317.66; Found, 1318.9 [M+H]+1. AnalyticalHPLC, Method 1B, R_(t)=15.410 min, Purity=73%.

Part D. Preparation of[2-[[[5-[carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}

To a solution ofGlu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe} (0.030 g,0.0183 mmol) in dimethylformamide (3 mL) was added triethylamine (7.6μL, 0.0549 mmol) and the reaction mixture was stirred for 5 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0096 g, 0.0220 mmol) was added, and thereaction mixture was stirred for 18 h, then concentrated to an oil underhigh vacuum. The oil was purified by Preparative HPLC Method 1 to give11.0 mg (32%) of the desired product as a lyophilized solid. ESMS:Calcd. for C₇₂H₉₆N₂₂O₂₀S, 1620.7; Found, 1620.1 (M−H⁺). Analytical HPLC,Method 1B, R_(t)==16.753 min, Purity=91%.

Example 7 Synthesis of[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Phe-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}

Part A. Preparation ofPhe-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}

A solution ofGlu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe} (23.4 mg,0.014 mmol) and triethylamine (7.8 μL, 0.56 mmol) in DMF (2 mL) wasstirred for 5 min. To this was added Boc-Phe-OSu (5.1 mg, 0.014 mmol)and the reaction mixture was stirred overnight at room temperature undernitrogen. DMF was removed in vacuo, and the resulting residue wasdissolved in TFA (1.5 mL) and methylene chloride (1.5 mL). The solutionwas stirred for 2 h and concentrated in vacuo to provide 31 mg of thedesired product as the TFA salt. ESMS: Calcd. for C₆₈H₉₆N₂₀O₁₇, 1464.7;Found, 1465.6 (M+H)+1. Analytical HPLC, Method 1B, R_(t)==15.48 min,Purity=95%.

Part B. Preparation of[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Phe-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}

To a solution ofPhe-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}(0.030 g, 0.016 mmol) in dimethylformamide (2 mL) was addedtriethylamine (9 μL, 15 0.064 mmol) and the reaction mixture was stirredfor 5 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0099 g, 0.0220 mmol) was added, and thereaction mixture was stirred for 18 h, then concentrated under highvacuum. The residue was purified by preparative RP-HPLC Method 1 to give7 mg (22%) of the desired product as a lyophilized solid (TFA salt).ESMS: Calcd. for C₈₁H₁₀₅N₂₃O₂₁S, 1767.8; Found, 1768.8 (M−H⁺).Analytical HPLC, Method 1B, R_(t)==17.68 min, Purity=99%.

Example 8 Synthesis ofcyclo{Arg-Gly-Asp-D-Nal-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Part A. Preparation of cyclo{Arg(Mtr)-Gly-Asp(OtBu)-D-Nal-Lys(Boc)}

The peptide Asp(OtBu)-D-Nal-Lys(Boc)-Arg(Mtr)-Gly was obtained byautomated solid phase peptide synthesis using Fmoc chemistry. A 100 mLround bottom flask was charged with HBTU (349 mg, 0.92 mmol) and DMF (10mL). The solution was stirred at 60° C. for 5 min. To this a solution ofAsp(OtBu)-D-Nal-Lys(Boc)Arg(Mtr)-Gly (0.684 g) and Hunig's base (0.34mL, 1.97 mmol.) in DMF (10 mL) was added and the solution stirred at 60°C. for 4 h under nitrogen. The solvent was then removed in vacuo and theresidue was triturated with ethyl acetate. The solids were filtered andwashed with ethyl acetate (3×5 mL) and dried in vacuo to give thedesired product (520 mg, 86%). ESMS: Calcd. for C₅₀H₇₁N₉O₁₂S, 1021.5;Found, 1022.5 [M+H]+1. Analytical HPLC, Method 1A, R_(t)=15.91 min(purity 99%).

Part B. Preparation of cyclo{Arg-Gly-Asp-D-Nal-Lys}bis TFA salt

A solution of cyclo{Arg(Mtr)-Gly-Asp(OtBu)-D-Nal-Lys(Boc)} (500 mg, 0.49mmol), TFA (7 mL), triisopropylsilane (0.25 mL) and water (0.25 mL) wasstirred at room temperature under nitrogen for 18 h. The solvents wereremoved in vacuo (over 3 h) and the residue triturated with diethylether to give the desired product as the TFA salt (426 mg, 98%). ESMS:Calcd. for C₃₁H₄₃N₉O₇, 653.3; Found, 654.3 [M+H]+1. Analytical HPLC,Method 1B, R_(t)=13.30 min, Purity=97%.

Part C. Preparation ofcyclo{Arg-Gly-Asp-D-Nal-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Cyclo{Arg-Gly-Asp-D-Nal-Lys}TFA salt (0.056 g, 0.064 mmol) was dissolvedin DMF (2 mL). Triethylamine (27 μL, 0.19 mmol) was added, and after 5min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]-hydrazono]-methyl]-benzenesulfonicacid, monosodium salt (0.039 g, 0.089 mmol) was added. The reactionmixture was stirred overnight, under nitrogen, and then concentrated toan oil under high vacuum. The oil was purified by Preparative HPLCMethod 1 to give 49.3 mg (72%) of the desired product as a lyophilizedsolid (TFA salt). ESMS: Calcd. for C₄₄H₅₂N₁₂O₁₁S, 956.4; Found, 957.5[M+H]+1. Analytical HPLC, Method 1B, R_(t)=16.19 min, Purity=99%.

Example 9 Synthesis of[2-[[[5-[carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal}

Part A. Preparation ofBoc-Glu(cyclo{Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal}

To a solution of cyclo{Lys-Arg-Gly-Asp-D-Nal} (0.052 g, 0.059 mmol) indimethylformamide (2 mL) was added triethylamine (25 μL). After stirringfor 5 minutes Boc-Glu(OSu)-OSu (0.013 g, 0.029 mmol) was added. Thereaction mixture was stirred under N₂ for 20 h, then concentrated to anoil under high vacuum and triturated with ethyl acetate. The productthus obtained was filtered, washed with ethyl acetate, and dried underhigh vacuum to give 35.2 mg of the desired product in crude form. ESMS:Calcd. for C₇₂H₉₉N₁₉O₁₈, 1517.7; Found, 760.1 [M+2H]+2. Analytical HPLC,Method 1B, R_(t)=21.07 min (65%).

Part B. Preparation ofGlu(cyclo{Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal}

To a solution of the crudeBoc-Glu(cyclo{Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal} (35.2mg) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5mL). The reaction mixture was stirred for 2 h, concentrated to an oilunder high vacuum and triturated with diethyl ether. The product wasfiltered, washed with diethyl ether, and dried under high vacuum to give34.9 mg of the crude desired product (TFA salt). ESMS: Calcd. forC₆₇H₉₁N₁₉O₁₆, 1417.69; Found, 1418.7 [M+H]+1. Analytical HPLC, Method1B, R_(t)=19.1 min, Purity=62%.

Part C. Preparation of[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal}

To a solution ofGlu(cyclo{Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal} (34.9 mg)in dimethylformamide (2 mL) was added triethylamine (10 μL, 0.074 mmol)and the reaction mixture was stirred for 5 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid, monosodium salt (15.2 mg, 0.0344 mmol) was added, and the reactionmixture was stirred for 18 h, then concentrated to an oil under highvacuum. The oil was purified by preparative RP-HPLC Method 1 to give 3mg of the desired product (TFA salt). ESMS: Calcd. for C₈₀H₁₀₀N₂₂O₂₀S,1720.7; Found, 1722.6 (M+H)+1. Analytical HPLC, Method 1B, R_(t)==19.78min, Purity=92%.

Example 10 Synthesis ofcyclo{Arg-Gly-Asp-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Val}

Part A. Preparation of cyclo{Arg(Tos)-Gly-Asp(OBzl)-Lys(Cbz)-D-Val}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-Lys(Z)-D-Val-Arg(Tos)-Gly-Oxime resin was removed usingstandard deprotection (25% TFA in CH₂Cl₂). After eight washes with DCM,the resin was treated with 10% DIEA/DCM (2×10 min.). The resin wassubsequently washed with DCM (×5) and dried under high vacuum. The resin(1.3229 g, 0.44 mmol/g) was then suspended in dimethylformamide (10 mL).Glacial acetic acid (33.3 μL, 0.582 mmol) was added, and the reactionwas heated at 65° C. for 72 h. The resin was filtered, and washed withDMF (2×10 mL). The filtrate was concentrated to an oil under highvacuum. The resulting oil was triturated with ethyl acetate. The solidthus obtained was filtered, washed with ethyl acetate, dried under highvacuum, then purified by Preparative HPLC Method 2 to give 93.0 mg ofthe desired product as a lyophilized solid. ESMS: Calcd. forC₄₅H₅₉N₉O₁₁S, 933.41; Found, 934.5 [M+H]+1. Analytical HPLC, Method 1A,R_(t)=14.078 min, Purity=85%.

Preparative HPLC Method 2

Instrument: Rainin Rabbit; Dynamax software

Column: Vydac C-18 (21.2 mm×25 cm)

Detector: Knauer VWM

Flow Rate: 15 ml/min

Column Temp: RT

Mobile Phase:

A: 0.1% TFA in H₂O

B: 0.1%TFA in ACN/H₂O (9:1)

Gradient: Time (min) % A % B 0 80 20 20 0 100 30 0 100 31 80 20

Part B. Preparation of cyclo{Arg-Gly-Asp-Lys-D-Val}

Cyclo{Arg(Tos)-Gly-Asp(OBzl)-Lys(Cbz)-D-Val} (0.080 g, 0.0856 mmol) wasdissolved in trifluoroacetic acid (0.6 mL) and cooled to −10° C.Trifluoromethanesulfonic acid (0.5 mL) was added dropwise, maintainingthe temperature at −10° C. Anisole (0.1 mL) was added and the reactionmixture was stirred at −10° C. for 3 h. Diethyl ether was added, thereaction mixture cooled to −50° C. and stirred for 30 mins. The crudeproduct obtained was filtered, washed with ether, dried under highvacuum and purified by Preparative HPLC Method 1, to give 44.2 mg (66%)of the desired product as a lyophilized solid. ESMS: Calcd. forC₂₃H₄₁N₉O₇, 555.31; Found, 556.3 [M+H]+1. Analytical HPLC, Method 1B,R_(t)=8.959 min, Purity=92%.

Part C. Preparation ofcyclo{Arg-Gly-Asp-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Val}

To a solution of cyclo{Arg-Gly-Asp-Lys-D-Val} (0.036 g, 0.0459 mmol) indimethylformamide (3 mL) was added triethylamine (19.2 μL, 0.0138 mmol)and stirred for 5 min. Methyl sulfoxide was added (0.7 mL) followed by2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0243 g, 0.0551 mmol) and the reaction mixturestirred for 20 h. The reaction mixture was concentrated to an oil underhigh vacuum and purified by Preparative HPLC Method 1 to give 13.9 mg(31%) of the desired product as a lyophilized solid. HRMS: Calcd. forC₃₆H₅₀N₁₂O₁₁S+H, 859.3443; Found, 859.3503. Analytical HPLC, Method 1B,R_(t)=13.479 min, Purity=92%.

Example 11 Synthesis of[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-D-Val-Arg-Gly-Asp})-cyclo{Lys-D-Val-Arg-Gly-Asp}

Part A. Preparation ofBoc-Glu(cyclo{Lys-D-Val-Arg-Gly-Asp})-cyclo{Lys-D-Val-Arg-Gly-Asp}

To a solution of cyclo{Lys-D-Val-Arg-Gly-Asp} (0.400 g, 0.51 mmol) indimethylformamide (7 mL) was added triethylamine (0.21 mL, 1.53 mmol).After stirring for 5 minutes Boc-Glu(OSu)-OSu (115 mg, 0.26 mmol) wasadded. The reaction mixture was stirred under N₂ for 20 h, thenconcentrated to an oil. The product thus obtained was partially purifiedby preparative RP-HPLC to give 124 mg of product. ESMS: Calcd. forC₅₆H₉₅N₁₉O₁₈, 1321.71; Found, 1322.6 [M+H]+1.

Part B. Preparation ofGlu(cyclo{Lys-D-Val-Arg-Gly-Asp})-cyclo{Lys-D-Val-Arg-Gly-Asp}

To a solution of the impureBoc-Glu(cyclo{Lys-D-Val-Arg-Gly-Asp})-cyclo{Lys-D-Val-Arg-Gly-Asp}(0.124 g) in methylene chloride (5 mL) was added trifluoroacetic acid (5mL). The reaction mixture was stirred for 2 h, concentrated to an oilunder high vacuum and triturated with diethyl ether. The product wasfiltered, washed with diethyl ether, and dried under high vacuum to give16.2 mg of the desired product after RP-HPLC (TFA salt). ESMS: Calcd.for C₅₁H₈₇N₁₉O₁₆, 1221.66; Found, 1222.6 [M+H]+1. Analytical HPLC,Method 1B, R_(t)=11.43 min, Purity=93%.

Part C. Preparation of[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-D-Val-Arg-Gly-Asp})-cyclo{Lys-D-Val-Arg-Gly-Asp}

To a solution ofGlu(cyclo{Lys-D-Val-Arg-Gly-Asp})-cyclo{Lys-D-Val-Arg-Gly-Asp} (0.016 g,0.01 mmol) in dimethylformamide (2 mL) was added triethylamine (4.2 μL)and the reaction mixture was stirred for 5 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0063 g, 0.014 mmol) was added, and the reactionmixture was stirred for 18 h, then concentrated to an oil under highvacuum. The residue was purified by preparative RP-HPLC Method 1 to givethe desired product (TFA salt). ESMS: Calcd. for C₆₄H₉₆N₂₂O₂₀S, 1524.7;Found, 1525.7 (M+H)+1. Analytical HPLC, Method 1B, R_(t)==13.20 min,Purity=99%.

Example 12 Synthesis of{cyclo(Arg-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}

Part A: Preparation ofcyclo{Arg(Tos)-D-Val-D-Tyr(N-Cbz-3-aminopropyl)-D-Asp(OBzl)-Gly}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Arg(Tos)-D-Val-D-Tyr(N-Cbz-aminopropyl)-D-Asp(OBzl)-Gly-Oxime resinwas removed using standard deprotection (50% TFA in CH₂Cl₂). Afterwashing with DCM (8×), the resin was neutralized with 10% DIEA/DCM (2×10min). The resin was washed with DCM (5×) and dried under high vacuumovernight. The resin (1.08 g, 0.36 mmol/g) was then suspended inN,N-dimethylformamide (12 mL). Glacial acetic acid (67 mL, 1.16 mmol)was added and the reaction mixture was heated to 55° C. for 72 h. Theresin was filtered and washed with DMF (3×10 mL). The filtrate wasconcentrated under high vacuum to give an oil. The resulting oil wastriturated with ethyl acetate. The solid obtained was purified byreverse-phase HPLC (Vydac C18 column, 18 to 90% acetonitrile gradientcontaining 0.1% TFA, R_(t)=15.243 min) to afford 101 mg of a whitepowdered product (30%). ESMS: Calculated for C₄₄H₅₇N₉O₁₂S, 935.3847Found 936.5 [M+H]+1.

Part B: Preparation of cyclo{Arg-D-Val-D-Tyr(3-aminopropyl)-D-Asp-Gly}

The protected cyclic peptidecyclo{Arg(Tos)-D-Val-D-Tyr(N-Cbz-3-aminopropyl)-D-Asp(OBzl)-Gly} (90 mg,0.0961 mmol) was dissolved in trifluoroacetic acid (0.95 mL) and cooledto −10° C. in a dry ice/acetone bath. To this solution was addedtrifluoromethanesulfonic acid (0.1.16 mmol), followed by anisole (190mL). The reaction mixture was stirred at −16° C. for 3 h. The dryice/acetone bath was then cooled to −35° C. and cold ether (40 mL) wasadded to the solution. The mixture was stirred for 30 min at −35° C.,then cooled to −50° C. and stirred for another 30 min. The crude productwas filtered, redissolved in water/acetonitrile (1/1), lyophilized, andpurified by reverse-phase HPLC (Vydac C18 Column, 1.8 to 90%acetonitrile gradient containing 0.1% TFA, R_(t)=13.383 min) to generate17 mg of the title product (27%). ESMS: Calculated for C₂₉H₄₅N₉O₈,647.3391 Found 648.2 [M+H]+1.

Part C: Preparation of{cyclo(Arg-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}

A solution of cyclo{Arg-D-Val-D-Tyr(3-aminopropyl)-D-Asp-Gly} (14 mg,0.0216 mmol) in N,N-dimethylformamide (2 mL) was added triethylamine (15mL, 0.108 mmol) and stirred at room temperature for 10 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl-2-pyridinyl]-hydrazono]methyl-benzenesulfonicacid, monosodium salt (11 mg, 0.0260 mmol) was added, and the mixturewas stirred for 18 h. The mixture was concentrated under high vacumm andthe residue was purified by reverse-phase HPLC (Vydac C18 Column, 1.8 to90% acetonitrile gradient containing 0.1% TFA, R_(t)=16.264 min) toafford 10 mg of a white powdered product (49%). ESMS: Calculated forC₄₂H₅₄N₁₂O₁₂S, 950.3705 Found 951.3 [M+H]+1.

Example 13 Synthesis ofcyclo{D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Phe-D-Asp-Gly-Arg}

Part A: Preparation of cyclo{D-Lys(Cbz)-D-Phe-D-Asp(OBzl)-Gly-Arg(Tos)}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Arg(Tos)-D-Lys(Cbz)-D-Phe-D-Asp(OBzl)-Gly-Oxime resin was removedusing standard deprotection (25% TFA in CH₂Cl₂). After eight washes withDCM, the resin was treated with 10% DIEA/DCM (2×10 min.). The resin wassubsequently washed with DCM (×5) and dried under high vacuum. The resin(1.93 g, 0.44 mmol/g) was then suspended in dimethylformamide (15 mL).Glacial acetic acid (77 μL) was added, and the reaction was heated to60° C. for 72 h. The resin was filtered, and washed with DMF (2×10 mL).The filtrate was concentrated to an oil under high vacuum. The resultingoil was triturated with ethyl acetate. The solid thus obtained wasfiltered, washed with ethyl acetate, and dried under high vacuum to givethe desired product which was then purified by preparative RP-HPLC(yield=252 mg). ESMS: Calcd. for C₄₉H₅₉N₉O₁₁S, 981.40; Found, 982.3[M+H]+1. Analytical HPLC, Method 1A, R_(t)=14.577 min.

Part B: Preparation of cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg}TFA salt

Cyclo{D-Lys(Cbz)-D-Phe-D-Asp(OBzl)-Gly-Arg(Tos)} (0.152 g, 0.155 mmol)was dissolved in trifluoracetic acid (1.55 mL) and cooled to −16° C.Trifluoromethanesulfonic acid (1.86 mL) was added dropwise, maintainingthe temperature at −16 °C. Anisole (0.31 mL) was added and the reactionwas stirred at −16° C. for 3 h. Diethyl ether was added, the reactionwas cooled to −35° C., and stirred for 20 min. The crude product wasfiltered, washed with diethyl ether, dried under high vacuum andpurified by Preparative HPLC Method 1, to give 69 mg (˜53%) of thedesired product as a lyophilized solid (TFA salt). ESMS: Calcd. forC₂₇H₄₁N₉O₇+H, 604.3207; Found, 604.4. Analytical HPLC, Method 1B,R_(t)=10.35 min, Purity=93%.

Part C: Preparation ofcyclo{D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Phe-D-Asp-Gly-Arg}TFA salt

Cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg}TFA salt (0.056 g, 0.0673 mmol) wasdissolved in DMF (2 mL). Triethylamine (28 μL, 0.202 mmol) was added,and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonicacid, monosodium salt (0.029 g, 0.0673 mmol) was added. The reactionmixture was stirred for 70 h and then concentrated to an oil under highvacuum. The oil was purified by preparative HPLC Method 1 to give 14 mg(78%) of the desired product as a lyophilized solid (TFA salt). ESMS:Calcd. for C₄₀H₅₀N₁₂O₁₁S+H, 907.3521; Found, 907.3. Analytical HPLC,Method 1B, R_(t)=14.17 min, Purity=99%.

Example 14 Synthesis of[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg}

Part A. Preparation ofBoc-Glu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg}

To a solution of cyclo(D-Lys-D-Phe-D-Asp-Gly-Arg) (0.190 g, 0.228 mmol)in dimethylformamide (5 mL) was added triethylamine (95 μL, 0.684 mmol).After stirring for 5 minutes Boc-Glu(OSu)-OSu (0.050 g, 0.114 mmol) wasadded. The reaction mixture was stirred under N₂ for 20 h, thenconcentrated to an oil under high vacuum and triturated with ethylacetate. The product thus obtained was filtered, washed with ethylacetate, and dried under high vacuum to give 172 mg of the desiredproduct in crude form. ESMS: Calcd. for C₆₄H₉₅N₁₉O₁₈, 1417.71; Found,1418.7 [M+H]+1. Analytical HPLC, Method 1B, R_(t)=16.8 min.

Part B. Preparation ofGlu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg}

To a solution of the crudeBoc-Glu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg}(0.172 g) in methylene chloride (4.5 mL) was added trifluoroacetic acid(4.5 mL). The reaction mixture was stirred for 2 h, concentrated to anoil under high vacuum and triturated with diethyl ether. The product wasfiltered, washed with diethyl ether, and dried under high vacuum to give38 mg of the desired product after RP-HPLC as a lyophilized solid (TFAsalt). ESMS: Calcd. for C₅₉H₈₇N₁₉O₁₆, 1317.66; Found, 1318.9 [M+H]+1.Analytical HPLC, Method 1B, R_(t)=13.06 min, Purity=93%.

Part C. Preparation of[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg}

To a solution ofGlu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg}(0.025 g, 0.015 mmol) in dimethylformamide (2 mL) was addedtriethylamine (6.3 μL, 0.045 mmol) and the reaction mixture was stirredfor 5 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0092 g, 0.0210 mmol) was added, and thereaction mixture was stirred for 18 h, then concentrated to an oil underhigh vacuum. The oil was purified by Preparative HPLC Method 1 to give12.5 mg of the desired product as a lyophilized solid (TFA salt). ESMS:Calcd. for C₇₂H₉₆N₂₂O₂₀S, 1620.7; Found, 1622.5 (M+H)+1. AnalyticalHPLC, Method 1B, R_(t)==14.62 min, Purity=96%.

Example 15 Synthesis ofcyclo{D-Phe-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Asp-Gly-Arg}

Part A. Preparation of cyclo{D-Phe-D-Lys(Cbz)-D-Asp(OBzl)-Gly-Arg(Tos)}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Arg(Tos)-D-Phe-D-Lys(Cbz)-D-Asp(OBzl)-Gly-Oxime resin was removedusing standard deprotection (25% TFA in CH₂Cl₂). After eight washes withDCM, the resin was treated with 10% DIEA/DCM (2×10 min.). The resin wassubsequently washed with DCM (×5) and dried under high vacuum. The resin(1.5 g, 0.44 mmol/g) was then suspended in dimethylformamide (12 mL).Glacial acetic acid (61 μL) was added, and the reaction was heated to60° C. for 72 h. The resin was filtered, and washed with DMF (2×10 mL).The filtrate was concentrated to an oil under high vacuum. The resultingoil was triturated with ethyl acetate. The solid thus obtained wasfiltered, washed with ethyl acetate, and dried under high vacuum to givethe desired product (yield 370 mg). ESMS: Calcd. for C₄₉H₅₉N₉O₁₁S,981.40; Found, 982.4 [M+H]+1. Analytical HPLC, Method 1A, R_(t)=14.32min (purity 60%).

Part B. Preparation of cyclo{D-Phe-D-Lys-D-Asp-Gly-Arg}bis TFA Salt

The crude cyclo{D-Phe-D-Lys(Cbz)-D-Asp(OBzl)-Gly-Arg(Tos)} (0.146 g) wasdissolved in trifluoracetic acid (1.5 mL) and cooled to −16° C.Trifluoromethanesulfonic acid (1.8 mL) was added dropwise, maintainingthe temperature at −16° C. Anisole (0.3 mL) was added and the reactionwas stirred at −16° C. for 3 h. Diethyl ether was added, the reactionwas cooled to −35° C., and stirred for 20 min. The crude product wasfiltered, washed with diethyl ether, dried under high vacuum andpurified by Preparative HPLC Method 1, to give 100 mg of the desiredproduct as a lyophilized solid (TFA salt). ESMS: Calcd. forC₂₇H₄₁N₉O₇+H, 604.3; Found, 604.3. Analytical HPLC, Method 1B,R_(t)=10.25 min, Purity=90%.

Part C. Preparation ofcyclo{D-Phe-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Asp-Gly-Arg}

Cyclo{D-Phe-D-Lys-D-Asp-Gly-Arg}TFA salt (0.090 g, 0.108 mmol) wasdissolved in DMF (2 mL). Triethylamine (45 μL, 0.324 mmol) was added,and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonicacid, monosodium salt (0.048 g, 0.108 mmol) was added. The reactionmixture was stirred for 70 h and then concentrated to an oil under highvacuum. The oil was purified by Preparative HPLC Method 1 to give 10 mgof the desired product as a lyophilized solid (TFA salt). ESMS: Calcd.for C₄₀H₅₀N₁₂O₁₁S+H, 907.4; Found, 907.3. Analytical HPLC, Method 1B,R_(t)=13.47 min, Purity=89%.

Example 16 Synthesis ofcyclo{N-Me-Arg-Gly-Asp-ATA-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Part A: Preparation of cyclo{N-Me-Arg(Tos)-Gly-Asp(OBzl)-ATA-D-Lys(Cbz)}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-ATA-D-Lys(Z)-N-Me-Arg(Tos)-Gly-Oxime resin was removedusing standard deprotection (50% TFA in CH₂Cl₂). After washing with DCM(8×), the resin was treated with 10% DIEA/DCM (2×10 min). The resin waswashed with DCM (5×) and dried under high vacuum overnight. The resin(1.24 g, 0.39 mmol/g) was then suspended in DMF (12 mL). Glacial aceticacid (67 mL, 1.16 mmol) was added and the reaction mixture was heated at50° C. for 72 h. The resin was filtered and washed with DMF (3×10 mL).The filtrate was concentrated under high vacuum to give an oil. Theresulting oil was triturated with ethyl acetate. The solid obtained waspurified by reverse-phase HPLC (Vydac C18 column, 18 to 90% acetonitrilegradient containing 0.1% TFA, R_(t)=14.129 min) to afford 42 mg (9%) ofthe desired product as a lyophilized solid. ESMS: Calculated forC₄₆H₅₆N₁₀O₁₁S₂, 988.3571 Found 989.4 [M+H]+1.

Part B: Preparation of cyclo{N-Me-Arg-Gly-Asp-ATA-D-Lys}

Cyclo{N-Me-Arg(Tos)-Gly-Asp(OBzl)-ATA-D-Lys(Cbz)} (36 mg, 0.0364 mmol)was dissolved in trifluoroacetic acid (0.364 mL) and cooled to −10° C.in a dry ice/acetone bath. To this solution was addedtrifluoromethanesulfonic acid (0.437 mmol), followed by anisole (70 mL).The reaction mixture was stirred at −10° C. for 3 h. The dry ice/acetonebath was then cooled to −35° C. and cold ether (40 mL) was added to thesolution. The mixture was stirred for 30 min at −35° C., then cooledfurther to −50° C. and stirred for another 30 min. The crude product wasfiltered, redissolved in water/acetonitrile (1/1), and lyophilized togenerate 35 mg of the title product (100%). ESMS: Calculated forC₂₄H₃₈N₁₀O₇S, 610.2646 Found 611.4 [M+H]+1.

Part C: Preparation ofcyclo{N-Me-Arg-Gly-Asp-ATA-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

To a solution of cyclo{N-Me-Arg-Gly-Asp-ATA-D-Lys} (31 mg, 0.051 mmol)in DMF (2 mL) was added triethylamine (28 mL, 0.204 mmol) and thereaction mixture stirred at room temperature for 10 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl-2-pyridinyl]hydrazono]methyl-benzenesulfonicacid, monosodium salt (27 mg, 0.0612 mmol) was added, the mixturestirred for 18 h and then concentrated under high vacumm. The residueobtained was purified by reverse-phase HPLC (Shandon HS-BDS column, 3 to10% acetonitrile, R_(t)=13.735 min) to afford 4 mg (8.8%) of the desiredproduct as a lyophilized solid. ESMS: Calculated for C₃₇H₄₇N₁₃O₁₁S₂,913.2959 Found 914.5 [M+H]+1.

Example 17 Synthesis ofcyclo{Cit-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Part A. Preparation of cyclo{Cit-Gly-Asp(OtBu)-D-Phe-Lys(Boc)}

The peptide Asp(OtBu)-D-Phe-Lys(Boc)-Cit-Gly was obtained by automatedsolid phase peptide synthesis using Fmoc chemistry (see generalprocedure). A 100 mL round bottom flask was charged with HBTU (271 mg,0.71 mmol) and DMF (10 mL). The solution was stirred at 60° C. for 5min. To this a solution of Asp(OtBu)-D-Phe-Lys(Boc)-Cit-Gly (0.456 g)and Hunig's base (0.27 mL, 1.53 mmol.) in DMF (10 mL) was added and thesolution stirred at 60° C. for 4 h under nitrogen. The solvent was thenremoved in vacuo and the residue was triturated with ethyl acetate. Thesolids were filtered and washed with ethyl acetate (3×6 mL) and dried invacuo to give the desired product (305 mg, 78%). ESMS: Calcd. forC₃₆H₅₆N₈O₁₀, 760.4; Found, 761.4 [M+H]+1. Analytical HPLC, Method 1A,R_(t)=11.8 min (purity 99%).

Part B. Preparation of cyclo{Cit-Gly-Asp(OtBu)-D-Phe-Lys(Boc)}

A solution of cyclo{Cit-Gly-Asp(OtBu)-D-Phe-Lys(Boc)}(287 mg, 0.38mmol), TFA (6 mL), triisopropylsilane (0.25 mL) and water (0.25 mL) wasstirred at room temperature under nitrogen for 4 h. The solvents wereremoved in vacuo (over 3 h) and the residue triturated with diethylether, filtered and washed with ether to give the desired product (315mg) (TFA salt). ESMS: Calcd. for C₂₇H₄₀N₈O₈, 604.3; Found, 605.4[M+H]+1. Analytical HPLC, Method 1B, R_(t)=9.6 min, Purity=97%.

Part C. Preparation ofcyclo{Cit-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Cyclo{Cit-Gly-Asp-D-Phe-Lys}TFA salt (0.044 g) was dissolved in DMF (2mL). Triethylamine (22 μL, 0.156 mmol) was added, and after 5 min ofstirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonicacid, monosodium salt (0.032 g, 0.073 mmol) was added. The reactionmixture was stirred overnight, under nitrogen, and then concentratedunder high vacuum. The residue was purified by preparative RP-HPLCMethod 1 to give 37 mg (70%) of the desired product as a lyophilizedsolid (TFA salt). ESMS: Calcd. for C₄₀H₄₉N₁₁O₁₂S, 907.3; Found, 908.4[M+H]+1. Analytical HPLC, Method 1B, R_(t)=14.15 min, Purity=99%.

Example 18A Synthesis oftris(t-butyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

Part A. Preparation of Phenylmethyl2-(1,4,7,10-Tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetate

A solution of tert-butyl(1,4,7,10-tetraaza-4,7-bis(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetate(0.922 g, 1.79 mmol), TEA (1.8 mL) and benzyl bromoacetate (0.86 mL,5.37 mmol) in anhydrous DMF (24 mL) was stirred at ambient temperaturesunder a nitrogen atmosphere for 24 h. The DMF was removed under vacuumand the resulting oil was dissolved in EtOAc (300 mL). This solution waswashed consecutively with water (2×50 mL) and saturated NaCl (50 mL),dried (MgSO₄), and concentrated to give the title compound as anamorphous solid (1.26 g). MS: m/e 663.5 [M+H].

Part B. Preparation of2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)aceticacid

The product from Part A, above (165 mg, 0.25 mmol) was hydrogenolyzedover 10% Pd on carbon (50 mg) in EtOH (15 mL) at 60 psi for 24 h. Thecatalyst was removed by filtration through filter aid and washed withEtOH. The filtrates were concentrated to give the title compound as anamorphous solid (134 mg, 94%). MS: m/e 573.5 [M+H].

Example 18 Synthesis of2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}

Part A. Preparation of2-(1,4,7,10-tetraaza-4,7,10-tris(t-butoxycarbonylmethyl)-1-cyclododecyl)acetyl-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}

To a solution oftris(t-butyl)-1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetraacetic acid(28 mg, 0.049 mmol) and Hunig's base (14 μL) in DMF (2 mL) was addedHBTU (17 mg, 0.0456 mmol) and the mixture stirred for 5 min. To this wasadded a solution ofGlu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe} (54.1 mg,0.0326 mmol) in DMF (1 mL) and the reaction mixture allowed to stirunder nitrogen at room temperature for 4 h. The solvent was removed invacuo and the residue purified by preparative RP-HPLC to give theproduct as a lyophilized solid (18.3 mg) (TFA salt). ESMS: Calcd. forC₈₇H₁₃₇N₂₃O₂₃, 1872.0; Found, 937.2 [M+2H]+2. Analytical HPLC, Method1B, R_(t)=19.98 min, Purity=99%.

Part B. Preparation of2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}

A solution of2-(1,4,7,10-tetraaza-4,7,10-tris(t-butoxycarbonylmethyl)-1-cyclododecyl)acetyl-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}(18.3 mg, 8.71 mmol) in TFA (3 mL) was stirred at room temperature undernitrogen for 5 h. The solution was concentrated in vacuo and the residuewas purified by preparative RP-HPLC to give 8 mg (45%) of the desiredproduct as the lyophilized solid (TFA salt). ESMS: Calcd. forC₇₅H₁₁₃N₂₃O₂₃, 1703.8; Found, 853.0 [M+2H]+2. Analytical HPLC, Method1B, R_(t)=13.13 min, Purity=99%.

Example 19 Synthesis of cyclo{Arg-Gly-Asp-D-Phe-Lys(DTPA)}

To a solution of cyclo{Arg-Gly-Asp-D-Phe-Lys} (0.050 g, 0.0601 mmol) inDMF (2 mL) was added triethylamine (41.9 μL, 0.301 mmol). This solutionwas added dropwise over 4 h to a solution ofdiethylenetriaminepentaacetic dianhydride (0.1074 g, 0.301 mmol) in DMF(2 mL) and methyl sulfoxide (2 mL). The reaction mixture was thenstirred for 16 h, concentrated to an oil under high vacuum and purifiedby Preparative HPLC Method 1 to give 29.9 mg (46%) of the desiredproduct as a lyophilized solid. ESMS: Calcd. for C₄₁H₆₂N₁₂O₁₆, 978.4;Found, 977.5 (M−H⁺). Analytical HPLC, Method 1B, R_(t)=11.916 min.Purity=100%.

Example 20 Synthesis of cyclo{Arg-Gly-Asp-D-Phe-Lys}₂(DTPA)

The oil obtained in Example 9 upon purification by Preparative HPLCMethod 1, also gave 21.5 mg (21%) of the title product as a lyophilizedsolid. ESMS: Calcd. for C₆₈H₁₀₁N₂₁O₂₂, 1563.7; Found, 1562.8 (M−H⁺).Analytical HPLC, Method 1B, R_(t)=15.135 min, Purity=93%.

Example 21 Synthesis ofCyclo{Arg-Gly-Asp-D-Tyr(N-DTPA-3-aminopropyl)-Val}

To a solution of cyclo{Arg-Gly-Asp-D-Tyr(3-aminopropyl)-Val} (0.050 g,0.0571 mmol) in dimethylformamide (2 mL) was added triethylamine (39.8μL, 0.286 mmol). This solution was added dropwise over 5 h to a solutionof diethylenetriamine-pentaacetic dianhydride (0.1020 g, 0.286 mmol) inmethyl sulfoxide (2 mL). The reaction mixture was stirred for anadditional 18 h, then concentrated to an oil under high vacuum andpurified by Preparative HPLC Method 1 to give 41.9 mg (65%) of thedesired product as a lyophilized solid. ESMS: Calcd. for C₄₃H₆₆N₁₂O₁₇,1022.5; Found, 1021.4 (M−H⁺). Analytical HPLC, Method 1B, R_(t)=15.690min, Purity=96%.

Example 22 Synthesis ofcyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Part A: Preparation ofcyclo{Orn(d-N-1-Tos-2-Imidazolinyl)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Tyr(N-Cbz-aminopropyl)-Val-Orn(d-N-1-Tos-2-Imidazolinyl)-Gly-Oximeresin is removed using standard deprotection (25% TFA in CH₂Cl₂). Aftereight washes with DCM, the resin is treated with 10% DIEA/DCM (2×10min.). The resin is subsequently washed with DCM (×5) and dried underhigh vacuum. The resin (1.75 g, 0.55 mmol/g) is then suspended indimethylformamide (15 mL). Glacial acetic acid (55.0 μL, 0.961 mmol) isadded, and the reaction mixture is heated at 50° C. for 72 h. The resinis filtered, and washed with DMF (2×10 mL). The filtrate is concentratedto an oil under high vacuum. The resulting oil is triturated with ethylacetate. The solid is filtered, washed with ethyl acetate, and is driedunder high vacuum to obtain the desired product.

Part B: Preparation ofcyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Tyr(3-aminopropyl)-Val}.Trifluoroacetic acid salt

Cyclo{Orn(d-N-1-Tos-2-Imidazolinyl)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}(0.146 mmol) is dissolved in trifluoroacetic acid (0.6 mL) and cooled to−10° C. Trifluoromethanesulfonic acid (0.5 mL) is added dropwise,maintaining the temperature at −10° C. Anisole (0.1 mL) is added and thereaction mixture is stirred at −10° C. for 3 h. Diethyl ether is added,the reaction mixture cooled to −35° C. and then stirred for 30 min. Thereaction mixture is cooled further to −50° C. and stirred for 30 min.The crude product is filtered, washed with diethyl ether, dried underhigh vacuum, and is purified by preparative HPLC to obtain the desiredproduct.

Part C. Preparation ofcyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Tyr(3-aminopropyl)-Val)}trifluoroaceticacid salt (0.0228 mmol) is dissolved in DMF (1 mL). Triethylamine(0.0648 mmol) is added, and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0274 mmol) is added. The reaction mixture isstirred for 1-2 days, and then concentrated to an oil under high vacuum.The oil is purified by preparative HPLC to obtain the desired product.

Example 23 Synthesis ofcyclo{Lys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Part A: Preparation ofcyclo{Lys(Tfa)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Tyr(N-Cbz-aminopropyl)-Val-Lys(Tfa)-Gly-Oxime resin isremoved using standard deprotection (25% TFA in CH₂Cl₂). After eightwashes with DCM, the resin is treated with 10% DIEA/DCM (2×10 min.). Theresin is subsequently washed with DCM (×5) and dried under high vacuum.The resin (1.75 g, 0.55 mmol/g) is then suspended in dimethylformamide(15 mL). Glacial acetic acid (55.0 μL, 0.961 mmol) is added, and thereaction mixture is heated at 50° C. for 72 h. The resin is filtered,and washed with DMF (2×10 mL). The filtrate is concentrated to an oilunder high vacuum. The resulting oil is triturated with ethyl acetate.The solid thus obtained is filtered, washed with ethyl acetate, and isdried under high vacuum to obtain the desired product.

Part B: Preparation ofcyclo{Lys(Tfa)-Gly-Asp-D-Tyr(3-aminopropyl)-Val}Trifluoroacetic acidsalt.

Cyclo{Lys(Tfa)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val} (0.146mmol) is dissolved in trifluoroacetic acid (0.6 mL) and cooled to −10°C. Trifluoromethanesulfonic acid (0.5 mL) is added dropwise, maintainingthe temperature at −10° C. Anisole (0.1 mL) is added and the reactionmixture is stirred at −10° C. for 3 h. Diethyl ether is added, thereaction mixture cooled to −35° C. and then stirred for 30 min. Thereaction mixture is cooled further to −50° C. and stirred for 30 min.The crude product obtained is filtered, washed with diethyl ether, driedunder high vacuum, and is purified by preparative HPLC to obtain thedesired product.

Part C. Preparation ofcyclo{Lys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Cyclo{Lys(Tfa)-Gly-Asp-D-Tyr(3-aminopropyl)-Val}trifluoroacetic acidsalt (0.0228 mmol) is dissolved in DMF (1 mL). Triethylamine (0.0648mmol) is added, and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0274 mmol) is added. The reaction mixture isstirred for 1-2 days, and then concentrated to an oil under high vacuum.The oil is treated with 20% piperidine in DMF, and the crude material ispurified by preparative HPLC to obtain the desired product.

Example 24 Synthesis ofcyclo{Cys(2-aminoethyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Part A: Preparation ofcyclo{Cys(2-N-Tfa-aminoethyl)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Tyr(N-Cbz-aminopropyl)-Val-Cys(2-N-Tfa-aminoethyl)-Gly-Oximeresin is removed using standard deprotection (25% TFA in CH₂Cl₂). Aftereight washes with DCM, the resin is treated with 10% DIEA/DCM (2×10min.). The resin is subsequently washed with DCM (×5) and dried underhigh vacuum. The resin (1.75 g, 0.55 mmol/g) is then suspended indimethylformamide (15 mL). Glacial acetic acid (55.0 μL, 0.961 mmol) isadded, and the reaction mixture is heated at 50° C. for 72 h. The resinis filtered, and washed with DMF (2×10 mL). The filtrate is concentratedto an oil under high vacuum. The resulting oil is triturated with ethylacetate. The solid thus obtained is filtered, washed with ethyl acetate,and dried under high vacuum to obtain the desired product.

Part B: Preparation ofcyclo{Cys(2-N-Tfa-aminoethyl)-Gly-Asp-D-Tyr(3-aminopropyl)-Val}.Trifluoroacetic acid salt

Cyclo{Cys(2-N-Tfa-aminoethyl)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}(0.146 mmol) is dissolved in trifluoroacetic acid (0.6 mL) and cooled to−10° C. Trifluoromethanesulfonic acid (0.5 mL) is added dropwise,maintaining the temperature at −10° C. Anisole (0.1 mL) is added and thereaction mixture is stirred at −10° C. for 3 h. Diethyl ether is added,the reaction mixture cooled to −35° C. and then stirred for 30 min. Thereaction mixture is cooled further to −50° C. and stirred for 30 min.The crude product obtained is filtered, washed with diethyl ether, driedunder high vacuum, and is purified by preparative HPLC to obtain thedesired product.

Part C. Preparation ofcyclo{Cys(2-aminoethyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Cyclo{Cys(2-N-Tfa-aminoethyl)-Gly-Asp-D-Tyr(3-aminopropyl)-Val}trifluoroaceticacid salt (0.0228 mmol) is dissolved in DMF (1 mL). Triethylamine (9.5μL, 0.0648 mmol) is added, and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0121 g, 0.0274 mmol) is added. The reactionmixture is stirred for 1-2 days, and then concentrated to an oil underhigh vacuum. The oil is treated with 20% piperidine in DMF, and thecrude material is purified by preparative HPLC to obtain the desiredproduct.

Example 25 Synthesis ofcyclo{HomoLys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Part A: Preparation ofcyclo{HomoLys(Tfa)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Tyr(N-Cbz-aminopropyl)-Val-HomoLys(Tfa)-Gly-Oxime resinis removed using standard deprotection (25% TFA in CH₂Cl₂). After eightwashes with DCM, the resin is treated with 10% DIEA/DCM (2×10 min.). Theresin is subsequently washed with DCM (×5) and dried under high vacuum.The resin (1.75 g, 0.55 mmol/g) is then suspended in dimethylformamide(15 mL). Glacial acetic acid (55.0 μL, 0.961 mmol) is added, and thereaction mixture is heated at 50° C. for 72 h. The resin is filtered,and washed with DMF (2×10 mL). The filtrate is concentrated to an oilunder high vacuum. The resulting oil is triturated with ethyl acetate.The solid thus obtained is filtered, washed with ethyl acetate, anddried under high vacuum to obtain the desired product.

Part B: Preparation ofcyclo{HomoLys(Tfa)-Gly-Asp-D-Tyr(3-aminopropyl)-Val}, Trifluoroaceticacid salt.

Cyclo{HomoLys(Tfa)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val} (0.146mmol) is dissolved in trifluoroacetic acid (0.6 mL) and cooled to −10°C. Trifluoromethanesulfonic acid (0.5 mL) is added dropwise, maintainingthe temperature at −10° C. Anisole (0.1 mL) is added and the reactionmixture is stirred at −10° C. for 3 h. Diethyl ether is added, thereaction mixture cooled to −35° C. and then stirred for 30 min. Thereaction mixture is cooled further to −50° C. and stirred for 30 min.The crude product obtained is filtered, washed with diethyl ether, driedunder high vacuum, and is purified by preparative HPLC to obtain thedesired product.

Part C. Preparation ofcyclo{HomoLys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Cyclo{HomoLys(Tfa)-Gly-Asp-D-Tyr(3-aminopropyl)-Val}trifluoroacetic acidsalt (0.0228 mmol) is dissolved in DMF (1 mL). Triethylamine (9.5 μL,0.0648 mmol) is added, and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0121 g, 0.0274 mmol) is added. The reactionmixture is stirred for 1-2 days, and then concentrated to an oil underhigh vacuum. The oil is treated with 20% piperidine in DMF, and thecrude material is purified by preparative HPLC to obtain the desiredproduct.

Example 26 Synthesis ofcyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Part A: Preparation ofcyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Tyr(N-Cbz-aminopropyl)-Val-Orn(d-N-Benzylcarbamoyl)-Gly-Oximeresin is removed using standard deprotection (25% TFA in CH₂Cl₂). Aftereight washes with DCM, the resin is treated with 10% DIEA/DCM (2×10min.). The resin is subsequently washed with DCM (×5) and dried underhigh vacuum. The resin (1.75 g, 0.55 mmol/g) is then suspended indimethylformamide (15 mL). Glacial acetic acid (55.0 μL, 0.961 mmol) isadded, and the reaction mixture is heated at 50° C. for 72 h. The resinis filtered, and washed with DMF (2×10 mL). The filtrate is concentratedto an oil under high vacuum. The resulting oil is triturated with ethylacetate. The solid thus obtained is filtered, washed with ethyl acetate,and dried under high vacuum to obtain the desired product.

Part B: Preparation ofcyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Tyr(3-aminopropyl)-Val}.Trifluoroacetic acid salt

Cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}(0.146 mmol) is dissolved in trifluoroacetic acid (0.6 mL) and cooled to−10° C. Trifluoromethanesulfonic acid (0.5 mL) is added dropwise,maintaining the temperature at −10° C. Anisole (0.1 mL) is added and thereaction mixture is stirred at −10° C. for 3 h. Diethyl ether is added,the reaction mixture cooled to −35° C. and then stirred for 30 min. Thereaction mixture is cooled further to −50° C. and stirred for 30 min.The crude product obtained is filtered, washed with diethyl ether, driedunder high vacuum, and is purified by preparative HPLC to obtain thedesired product.

Part C. Preparation ofcyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Tyr(3-aminopropyl)-Val}trifluoroaceticacid salt (0.0228 mmol) is dissolved in DMF (1 mL). Triethylamine (9.5μL, 0.0648 mmol) is added, and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0121 g, 0.0274 mmol) is added. The reactionmixture is stirred for 1-2 days, and then concentrated to an oil underhigh vacuum. The oil is purified by preparative HPLC to obtain thedesired product.

Example 27 Synthesis ofcyclo{Dap(b-(2-benzimidazolylacetyl))-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Part A: Preparation ofcyclo{Dap(b-(1-Tos-2-benzimidazolylacetyl))-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Tyr(N-Cbz-aminopropyl)-Val-Dap(b-(1-Tos-2-benzimidazolylacetyl))-Gly-Oximeresin is removed using standard deprotection (25% TFA in CH₂Cl₂). Aftereight washes with DCM, the resin is treated with 10% DIEA/DCM (2×10min.). The resin is subsequently washed with DCM (×5) and dried underhigh vacuum. The resin (1.75 g, 0.55 mmol/g) is then suspended indimethylformamide (15 mL). Glacial acetic acid (55.0 μL, 0.961 mmol) isadded, and the reaction mixture is heated at 50° C. for 72 h. The resinis filtered, and washed with DMF (2×10 mL). The filtrate is concentratedto an oil under high vacuum. The resulting oil is triturated with ethylacetate. The solid thus obtained is filtered, washed with ethyl acetate,and dried under high vacuum to obtain the desired product.

Part B: Preparation ofcyclo{Dap(b-(2-benzimidazolylacetyl))-Gly-Asp-D-Tyr(3-aminopropyl)-Val}.Trifluoroaceticacid salt

Cyclo{Dap(b-(1-Tos-2-benzimidazolylacetyl))-Gly-Asp(OBzl)-D-Tyr(N-Cbz-3-aminopropyl)-Val}(0.146 mmol) is dissolved in trifluoroacetic acid (0.6 mL) and cooled to−10° C. Trifluoromethanesulfonic acid (0.5 mL) is added dropwise,maintaining the temperature at −10° C. Anisole (0.1 mL) is added and thereaction mixture is stirred at −10° C. for 3 h. Diethyl ether is added,the reaction mixture cooled to −35° C. and then stirred for 30 min. Thereaction mixture is cooled further to −50° C. and stirred for 30 min.The crude product obtained is filtered, washed with diethyl ether, driedunder high vacuum, and purified by preparative HPLC to obtain thedesired product.

Part C. Preparation ofcyclo{Dap(b-(2-benzimidazolylacetyl))-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}

Cyclo{Dap(b-(2-benzimidazolylacetyl))-Gly-Asp-D-Tyr(3-aminopropyl)-Val}trifluoroaceticacid salt (0.0228 mmol) is dissolved in DMF (1 mL). Triethylamine (9.5μL, 0.0648 mmol) is added, and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid, monosodium salt (0.0121 g, 0.0274 mmol) is added. The reactionmixture is stirred for 1-2 days, and then concentrated to an oil underhigh vacuum. The oil is purified by the method described below to obtainthe desired product.

Example 28 Synthesis ofcyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Part A: Preparation ofcyclo{Orn(d-N-1-Tos-2-Imidazolinyl)-Gly-Asp(OBzl)-D-Phe-Lys(Cbz)}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Phe-Lys(Z)-Orn(d-N-1-Tos-2-Imidazolinyl)-Gly-Oxime resinis removed using standard deprotection (25% TFA in CH₂Cl₂). After eightwashes with DCM, the resin is treated with 10% DIEA/DCM (2×10 min.). Theresin is subsequently washed with DCM (×5) and dried under high vacuum.The resin (1.75 g, 0.55 mmol/g) is then suspended in dimethylformamide(15 mL). Glacial acetic acid (55.0 μL, 0.961 mmol) is added, and thereaction mixture is heated at 50° C. for 72 h. The resin is filtered,and washed with DMF (2×10 mL). The filtrate is concentrated to an oilunder high vacuum. The resulting oil is triturated with ethyl acetate.The solid thus obtained is filtered, washed with ethyl acetate, anddried under high vacuum to obtain the desired product.

Part B. Preparation of cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Phe-Lys}

Cyclo{Orn(d-N-1-Tos-2-Imidazolinyl)-Gly-Asp(OBzl)-D-Phe-Lys(Cbz)} (0.204mmol) is dissolved in trifluoroacetic acid (0.6 mL) and cooled to −10°C. Trifluoromethanesulfonic acid (0.5 mL) is added dropwise, maintainingthe temperature at −10° C. Anisole (0.1 mL) is added and the reaction isstirred at −10° C. for 3 h. Diethyl ether is added, the reaction iscooled to −50° C., and stirred for 1 h. The crude product is filtered,washed with diethyl ether, dried under high vacuum and purified bypreparative HPLC to obtain the desires product.

Part C. Preparation ofcyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Phe-Lys}TFA salt (0.0481 mmol)is dissolved in DMF (2 mL). Triethylamine (20.1 μL, 0.144 mmol) isadded, and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonicacid, monosodium salt (0.0254 g, 0.0577 mmol) is added. The reactionmixture is stirred for 20 h and then concentrated to an oil under highvacuum. The oil is purified by preparative HPLC to obtain the desiredproduct.

Example 29 Synthesis ofcyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Part A: Preparation ofcyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp(OBzl)-D-Phe-Lys(Cbz)}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Asp(OBzl)-D-Phe-Lys(Z)-Orn(d-N-Benzylcarbamoyl)-Gly-Oxime resin isremoved using standard deprotection (25% TFA in CH₂Cl₂). After eightwashes with DCM, the resin is treated with 10% DIEA/DCM (2×10 min.). Theresin is subsequently washed with DCM (×5) and dried under high vacuum.The resin (1.75 g, 0.55 mmol/g) is then suspended in dimethylformamide(15 mL). Glacial acetic acid (55.0 μL, 0.961 mmol) is added, and thereaction mixture is heated at 50° C. for 72 h. The resin is filtered,and washed with DMF (2×10 mL). The filtrate is concentrated to an oilunder high vacuum. The resulting oil is triturated with ethyl acetate.The solid thus obtained is filtered, washed with ethyl acetate, anddried under high vacuum to obtain the desired product.

Part B. Preparation of cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Phe-Lys}

Cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp(OBzl)-D-Phe-Lys(Cbz)} (0.204mmol) is dissolved in trifluoroacetic acid (0.6 mL) and cooled to −10°C. Trifluoromethanesulfonic acid (0.5 mL) is added dropwise, maintainingthe temperature at −10° C. Anisole (0.1 mL) is added and the reaction isstirred at −10° C. for 3 h. Diethyl ether is added, the reaction iscooled to −50° C., and stirred for 1 h. The crude product is filtered,washed with diethyl ether, dried under high vacuum and purified bypreparative HPLC to obtain the desires product.

Part C. Preparation ofcyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}

Cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Phe-Lys}TFA salt (0.0481 mmol)is dissolved in DMF (2 mL). Triethylamine (20.1 μL, 0.144 mmol) isadded, and after 5 min of stirring2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonicacid, monosodium salt (0.0254 g, 0.0577 mmol) is added. The reactionmixture is stirred for 20 h and then concentrated to an oil under highvacuum. The oil is purified by preparative HPLC to obtain the desiredproduct.

Example 30 Synthesis ofcyclo{Lys-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}

A: Preparation ofcyclo{Lys(Tfa)-D-Val-D-Tyr(N-Cbz-3-aminopropyl)-D-Asp(OBzl)-Gly}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Lys(Tfa)-D-Val-D-Tyr(N-Cbz-aminopropyl)-D-Asp(OBzl)-Gly-Oxime resinis removed using standard deprotection (50% TFA in CH₂Cl₂). Afterwashing with DCM (8×), the resin is neutralized with 10% DIEA/DCM (2×10min). The resin is washed with DCM (5×) and dried under high vacuumovernight. The resin (1.0 g, about 0.36 mmol/g) is then suspended inN,N-dimethylformamide (12 mL). Glacial acetic acid (67 mL, 1.16 mmol) isadded and the reaction mixture is heated to 55° C. for 72 h. The resinis filtered and washed with DMF (3×10 mL). The filtrate is concentratedunder high vacuum to give an oil. The resulting oil is triturated withethyl acetate. The desired product is purified by reverse-phase HPLC.

Part B: Preparation of cyclo{Lys-D-Val-D-Tyr(3-aminopropyl)-D-Asp-Gly},Trifuoroacetic acid salt

The protected cyclic peptidecyclo{Lys(Tfa)-D-Val-D-Tyr(N-Cbz-3-aminopropyl)-D-Asp(OBzl)-Gly} (0.10mmol) is dissolved in trifluoroacetic acid (0.9.5 mL) and cooled to −10°C. in a dry ice/acetone bath. To this solution is addedtrifluoromethanesulfonic acid (0.12 mmol), followed by anisole (190 mL).The reaction mixture is stirred at −16° C. for 3 h. The dry ice/acetonebath is then cooled to −35° C. and cold ether (40 mL) is added to thesolution. The mixture is stirred for 30 min at −35° C., then cooled to−50° C. and stirred for another 30 min. The crude product is filtered,redissolved in water/acetonitrile (1/1), lyophilized, and purified byreverse-phase HPLC to give the desired product.

Part C: Preparation ofcyclo{Lys-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}

A solution of cyclo{Lys(Tfa)-D-Val-D-Tyr(3-aminopropyl)-D-Asp-Gly}(0.0216 mmol) in N,N-dimethylformamide (2 mL) is added triethylamine (15mL, 0.108 mmol) and stirred at room temperature for 10 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl-2-pyridinyl]hydrazono]methyl-benzenesulfonicacid, monosodium salt (0.0260 mmol) is added, and the mixture is stirredfor 18 h. The mixture is concentrated under high vacumm, the oil istreated with 20% piperidine in DMF, and is again concntrated in vacuo.The residue is purified by reverse-phase HPLC to give the desiredproduct.

Example 31 Synthesis ofcyclo{Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}

Part A: Preparation ofcyclo{Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(N-Cbz-3-aminopropyl)-D-Asp(OBzl)-Gly}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(N-Cbz-aminopropyl)-D-Asp(OBzl)-Gly-Oximeresin is removed using standard deprotection (50% TFA in CH₂Cl₂). Afterwashing with DCM (8×), the resin is neutralized with 10% DIEA/DCM (2×10min). The resin is washed with DCM (5×) and dried under high vacuumovernight. The resin (1.0 g, about 0.36 mmol/g) is then suspended inN,N-dimethylformamide (12 mL). Glacial acetic acid (67 mL, 1.16 mmol) isadded and the reaction mixture is heated to 55° C. for 72 h. The resinis filtered and washed with DMF (3×10 mL). The filtrate is concentratedunder high vacuum to give an oil. The resulting oil is triturated withethyl acetate. The desired product is purified by reverse-phase HPLC.

Part B: Preparation ofcyclo{Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(3-aminopropyl)-D-Asp-Gly},Trifuoroacetic acid salt

The protected cyclic peptidecyclo{Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(N-Cbz-3-aminopropyl)-D-Asp(OBzl)-Gly}(0.10 mmol) is dissolved in trifluoroacetic acid (0.95 mL) and cooled to−10° C. in a dry ice/acetone bath. To this solution is addedtrifluoromethanesulfonic acid (0.12 mmol), followed by anisole (190 mL).The reaction mixture is stirred at −16° C. for 3 h. The dry ice/acetonebath is then cooled to −35° C. and cold ether (40 mL) is added to thesolution. The mixture is stirred for 30 min at −35° C., then cooled to−50° C. and stirred for another 30 min. The crude product is filtered,redissolved in water/acetonitrile (1/1), lyophilized, and purified byreverse-phase HPLC to give the desired product.

Part C: Preparation ofcyclo{Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}

A solution ofcyclo{Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(3-aminopropyl)-D-Asp-Gly}(0.0216 mmol) in N,N-dimethylformamide (2 mL) is added triethylamine (15mL, 0.108 mmol) and stirred at room temperature for 10 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl-2-pyridinyl]hydrazono]methyl-benzenesulfonicacid, monosodium salt (0.0260 mmol) is added, and the mixture is stirredfor 18 h. The mixture is concentrated under high vacumm and the residueis purified by reverse-phase HPLC to give the desired product.

Example 32 Synthesis ofcyclo{Orn(d-N-2-Imidazolinyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}

Part A: Preparation ofcyclo{Orn(d-N-1-Tos-2-Imidazolinyl)-D-Val-D-Tyr(N-Cbz-3-aminopropyl)-D-Asp(OBzl)-Gly}

The N-terminus Boc-protecting group of the peptide sequenceBoc-Orn(d-N-1-Tos-2-Imidazolinyl)-D-Val-D-Tyr(N-Cbz-aminopropyl)-D-Asp(OBzl)-Gly-Oximeresin is removed using standard deprotection (50% TFA in CH₂Cl₂). Afterwashing with DCM (8×), the resin is neutralized with 10% DIEA/DCM (2×10min). The resin is washed with DCM (5×) and dried under high vacuumovernight. The resin (1.0 g, about 0.36 mmol/g) is then suspended inN,N-dimethylformamide (12 mL). Glacial acetic acid (67 mL, 1.16 mmol) isadded and the reaction mixture is heated to 55° C. for 72 h. The resinis filtered and washed with DMF (3×10 mL). The filtrate is concentratedunder high vacuum to give an oil. The resulting oil is triturated withethyl acetate. The desired product is purified by reverse-phase HPLC.

Part B: Preparation ofcyclo{Orn(d-N-2-Imidazolinyl)-D-Val-D-Tyr(3-aminopropyl)-D-Asp-Gly},Trifuoroacetic acid salt

The protected cyclic peptidecyclo{Orn(d-N-1-Tos-2-Imidazolinyl)-D-val-D-Tyr(N-Cbz-3-aminopropyl)-D-Asp(OBzl)-Gly}(0.10 mmol) is dissolved in trifluoroacetic acid (0.95 mL) and cooled to−10° C. in a dry ice/acetone bath. To this solution is addedtrifluoromethanesulfonic acid (0.12 mmol), followed by anisole (190 mL).The reaction mixture is stirred at −16° C. for 3 h. The dry ice/acetonebath is then cooled to −35° C. and cold ether (40 mL) is added to thesolution. The mixture is stirred for 30 min at −35° C., then cooled to−50° C. and stirred for another 30 min. The crude product is filtered,redissolved in water/acetonitrile (1/1), lyophilized, and purified byreverse-phase HPLC to give the desired product.

Part C: Preparation ofcyclo{Orn(d-N-2-Imidazolinyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}

A solution ofcyclo{Orn(d-N-2-Imidazolinyl)-D-Val-D-Tyr(3-aminopropyl)-D-Asp-Gly}(0.0216 mmol) in N,N-dimethylformamide (2 mL) is added triethylamine (15mL, 0.108 mmol) and stirred at room temperature for 10 min.2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl-2-pyridinyl]-hydrazono]methyl-benzenesulfonicacid, monosodium salt (0.0260 mmol) is added, and the mixture is stirredfor 18 h. The mixture is concentrated under high vacumm and the residueis purified by reverse-phase HPLC to give the desired product.

Radiopharmaceutical Examples

The following procedures (A, B) describe the synthesis ofradiopharmaceuticals of the present invention of the formula^(99m)Tc(VnA)(tricine)(phosphine), in which (VnA) represents thevitronectin receptor antagonist compound bonded to the Tc through adiazenido (—N═N—) or hydrazido (═N—NH—) moiety. The diazenido orhydrazido moiety results from the reaction of the hydrazinonicotinamidogroup, present either as the free hydrazine or protected as a hydrazone,with the Tc-99m. The other two ligands in the Tc coordination sphere aretricine and a phosphine.

Procedure A Synthesis of Tc-99m Vitronectin Receptor AntagonistComplexes of the Formula ^(99m)Tc(VnA)(tricine)(phosphine) UsingStannous Reducing Agent

10-30 μg (0.2-0.4 mL) of a reagent of the present invention dissolved insaline or 50% aqueous ethanol, 40 mg (0.4 mL) of tricine in water, 1-7mg (0.10-0.30 mL) of phosphine dissolved in water or ethanol, 25 μg (25μL) SnCl₂.2H₂O dissolved in 0.1 M HCl, 0-0.25 mL ethanol and 50-150 mCi^(99m)TcO₄− in saline were combined in a 10 cc vial. The kit was heatedin a 100° C. water bath for 10-20 minutes, then a 50 μL sample analyzedby HPLC Method 3. If necessary, the complex was purified by performing a300-400 μL injection on the HPLC and collecting the fraction into ashielded flask. The collected fraction was evaporated to dryness,redissolved in saline containing 0-5 vol % Tween 80, and thenre-analyzed using HPLC Method 3.

Procedure B Synthesis of Tc-99m Vitronectin Receptor AntagonistComplexes of the Formula ^(99m)Tc(VnA)(tricine)(TPPTS) without UsingStannous Reducing Agent

To a lyophilized vial containing 4.84 mg TPPTS, 6.3 mg tricine, 40 mgmannitol and 0.25 mmol succinate buffer, pH 4.8, was added 0.2-0.4 mL(20-40 μg) of a reagent of the present invention dissolved in saline or50% aqueous ethanol, 50-100 mCi ^(99m)TcO₄− in saline, and additionalsaline to give a total volume of 1.3-1.5 mL. The kit is heated in an100° C. water bath for 10-15 minutes, and a sample was then analyzed byHPLC Method 3. If necessary, the complex was purified by performing a300-400 μL injection on the HPLC and collecting the fraction into ashielded flask. The collected fraction was evaporated to dryness,redissolved in saline containing 0-5 vol% Tween 80, and then re-analyzedusing HPLC Method 3.

TABLE 1 Analytical and Yield Data for ^(99m)Tc(VnA) (tricine)(Phosphine) Complexes Complex Ex. Reagent Ex. No. No. Phosphine % YieldRT (min) 33 1 TPPTS 88 8.2 34 2 TPPTS 96 19.5 35 3 TPPTS 91 33.7 36 4TPPTS 92 21.8 37 5 TPPTS 65 25.1 38 6 TPPTS 91 41.7 39 7 TPPTS 89 20.440 8 TPPTS 93 16.4 41 9 TPPTS 90 13.4 42 10 TPPTS 93 12.9 43 12 TPPMS 9423.5 44 12 TPPDS 93 18.1 45 12 TPPTS 93 13.6 46 13 TPPTS 93 11.2 47 14TPPTS 79 11.0 48 15 TPPTS 94 11.2 49 16 TPPTS 81 9.2 50 17 TPPTS 97 10.4

The following example describes the synthesis of radiopharmaceuticals ofthe present invention of the formula ^(99m)Tc (VnA)(tricine)(L)(L=Imine-Nitrogen Containing Heterocycle), in which (VnA) represents thevitronectin receptor antagonist compound bonded to the Tc through adiazenido (—N═N—) or hydrazido (═N—NH—) moiety. The other two ligands inthe Tc coordination sphere are tricine and an imine-nitrogen containingheterocycle.

Example 51 Synthesis of Tc-99m Vitronectin Receptor Antagonist Complex^(99m)Tc(VnA)(tricine)(1,2,4-triazole)

30 μg of the Reagent of Example 1 (0.30 mL 50/50 EtOH/H₂O), 40 mgtricine (0.25 mL/H₂O), 8 mg 1,2,4-triazole (0.25 mL/H₂O), 25 μg SnCl₂(25 μL/0.1 N HCl), 0.50 mL water and 0.20 mL 50±5 mCi ^(99m)TcO₄− werecombined in a shielded 10 cc vial and heated at 100° C. for 10 minutes.50 μL of the kit contents were analyzed by HPLC using Method listedbelow. The product eluted at a retention time of 8.33 min and had aradiochemical purity of 88.1%.

Reagents of the present invention comprised of either a DOTA (Example18), DTPA monoamide (Examples 19 and 20) or DTPA bisamide chelator(Example 21) readily form complexes with metal ions of elements 31, 39,49, and 58-71. The following examples demonstrate the synthesis ofcomplexes with ¹⁵³Sm, ¹⁷⁷Lu, and ⁹⁰Y, beta particle emitting isotopesused in radiopharmaceutical therapy, and ¹¹¹In, a gamma emitting isotopeused in radiopharmaceutical imaging agents. In both types of complexes,the metal ion is bound to the DOTA, DTPA monoamide or DTPA bisamidechelator moiety of the reagents.

Examples 52 and 53 Synthesis of Y-90 and Lu-177 DOTA-ContainingVitronectin Antagonist Complexes

To a clean sealed 10 mL vial was added 0.5 mL of the reagent of Example18 (200 μg/mL in 0.25 M ammonium acetate buffer, pH 7.0), followed by0.05-0.1 mL of gentisic acid (sodium salt, 10 mg/mL in 0.25 M ammoniumacetate buffer, pH 7.0) solution, 0.3 mL of 0.25 M ammonium acetatebuffer (pH 7.0), and 0.05 mL of ¹⁷⁷LuCl₃ solution or ⁹⁰YCl₃ solution(100-200 mCi/mL) in 0.05 N HCl. The resulting mixture was heated at 100°C. for 35 min. After cooling to room temperature, a sample of theresulting solution was analyzed by radio-HPLC and ITLC. The complex ofExample 53 was analyzed by mass spectroscopy (Found [M+H⁺]=1877.6,Calcd. 1875.8 for C₇₅H₁₁₀N₂₃O₂₃Lu) which confirmed identity.

Example 54 Synthesis of a ¹¹¹In DOTA-Containing Vitronectin AntagonistComplex

To a lead shielded 300 μL autosampler vial was added 50 μL of gentisicacid (10 mg/mL in 0.1 M ammonium acetate buffer, pH 6.75) solution,followed by 100 μL of the reagent of Example 18 (200 μg/mL in 0.2 Mammonium acetate buffer, pH 5.0), and 50 μL of ¹¹¹InCl₃ solution (10mCi/mL) in 0.04 N HCl. The pH of the reaction mixture was about 4.0. Thesolution was heated at 100° C. for 25 min. A sample of the resultingsolution was analyzed by radio-HPLC and ITLC.

Table 1A: Analytical and Yield Data for Y-90, In-111, and Lu-177Complexes of DOTA-Conjugated Vitronectin Receptor Antagonists.

Complex Ex. Reagent Ex. HPLC Ret. No. No. Isotope % Yield Time (min) 5218 Y-90 96 16.5 53 18 Lu-177 96 16.5 54 18 In-111 95 16.5

Examples 55 and 56 Synthesis of In-111 DTPA-monoamide or DTPA-bisamideContaining Vitronectin Antagonist Complexes

0.2 mL of ¹¹¹InCl₃ (1.7 mCi) in 0.1 N HCl, 0.2 mL of 1.0 M ammoniumacetate buffer (pH 6.9) and 0.1 ml of the reagent of the presentinvention dissolved in water were combined in a 10 cc glass vial andallowed to react at room temperature for 30 min. The reaction mixturewas analyzed by HPLC Method 3.

TABLE 2 Analytical and Yield Data for ¹¹¹In Complexes Complex Ex.Reagent Ex. HPLC Ret. No. No. % Yield Time (min) 55 19 86 11.1 56 20 9618.8

Examples 57-59 Synthesis of Sm-153 Vitronectin Antagonist Complexes

0.25 mL of a ¹⁵³SmCl₃ stock solution (54 mCi/μmol Sm, 40 mCi/mL) in 0.1N HCl was combined with the reagent of the present invention (50-foldmolar excess) dissolved in 1 N ammonium acetate buffer in a 10 cc glassvial. The reaction was allowed to proceed at room temperature for ˜30min and was then analyzed by ITLC and HPLC (Method 3). If necessary, thecomplex was purified by performing a 300-400 μL injection on the HPLCand collecting the fraction into a shielded flask. The collectedfraction was evaporated to dryness, redissolved in saline, and thenre-analyzed using HPLC Method 3.

TABLE 3 Analytical and Yield Data for ¹⁵³Sm Complexes Complex Ex.Reagent Ex. HPLC Ret. No. No. % Yield Time (min) 57 19 91 11.7 58 20 8413.1 59 21 96 16.9

The non-radioactive (naturally occurring) samarium analog of theRadiopharmaceutical of Example 59 was prepared by combining 3.3. mg (2.9μmol) of the Reagent of Example 21 dissolved in 2 mL of 1 M ammoniumacetate buffer, pH 7, and 0.29 mL of 0.01 M solution of SmCl₃ in 0.1 NHCl. The reaction was allowed to proceed for ˜5 h at room temperatureand then the product was isolated by HPLC Method 3. The volatiles wereremoved by lyophilization. The identity of the complex was confirmed bymass spectroscopy. (API-ESMS:Found [M+2H⁺=1172.4, Calcd. 1172.9 forC₄₃H₆₄N₁₂O₁₇Sm] A stock solution of the complex was made in water andits concentration determined by ICP analysis for use in determining thebinding affinity of the complex for the vitronectin receptor α_(v)β₃.

The structures of representative In-111 (Example 56), Y-90 (Example 52)and Sm-153 (Example 59) radiopharmaceuticals of the present inventionare shown below.

Examples 60-62 Synthesis of Lu-177 Vitronectin Antagonist Complexes

5×10⁻⁹ mol of a reagent of the present invention was dissolved in 1.0 mLof 0.1 N acetate buffer, pH 6.8. 1×10⁻⁹ mol of Lu-177 (40 μl, 3 mCi)dissolved in 0.1 N HCl was added and the reaction.allowed to proceed atroom temperature for 30-45 min. The reaction mixtures were analyzed byHPLC Method 3.

TABLE 4 Analytical and Yield Data for ¹⁷⁷Lu Complexes Complex Ex.Reagent Ex. HPLC Ret. No. No. % Yield Time (min) 60 19 98 11.0 61 20 9815.6 62 21 98 11.7

Example 63

The gadolinium complex of the reagent of Example 21 was preparedaccording to the following procedure. 3-3.5 mg of the reagent wasdissolved in 2 mL 1 M ammonium acetate buffer at pH 7.0, and oneequivalent Gd(NO₃)₃ solution (0.02 M in water) was added to it. Thereaction mixture was allowed to stay at room temperature for 3-5 hoursand the product was isolated by HPLC Method 4. The fraction containingthe complex was lyophilized and dissolved in 1 mL H₂O resulting in asolution approximately 2 mM in Gd as determined by ICP analysis. Theidentity of the complex was confirmed by mass spectroscopy.(API-ESMS:Found [M+2H⁺]=1176.9, Calcd. 1176.2 for C₄₃H₆₄N₁₂O₁₇Gd].

The following examples describe the synthesis of ultrasound contrastagents of the present invention comprised of targeting moieties fortumor neovasculature that are α_(v)β₃ receptor antagonists.

Example 64 Part A. Synthesis of1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-(cyclo(Arg-Gly-Asp-D-Phe-Lys)-dodecane-1,12-dione

A solution of disuccinimidyl dodecane-1,12-dioate (0.424 g, 1 mmol),1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (1.489 g, 1 mmol) andcyclo(Arg-Gly-Asp-D-Phe-Lys)TFA salt (0.831 g, 1 mmol) in 25 mlchloroform is stirred for 5 min. Sodium carbonate (1 mmol) and sodiumsulfate (1 mmol) are added and the solution is stirred at roomtemperature under nitrogen for 18 h. DMF is removed in vacuo and thecrude product is purified to obtain the title compound.

Part B. Preparation of Contrast Agent Composition

The Synthesis of1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-(cyclo(Arg-Gly-Asp-D-Phe-Lys)-dodecane-1,12-dioneis admixed with three other lipids,1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid,1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, andN-(methoxypolyethylene glycol 5000carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine inrelative amounts of 1 wt. %:6 wt. %:54 wt. %:41 wt. %. An aqueoussolution of this lipid admixture (1 mg/mL), sodium chloride (7 mg/mL),glycerin (0.1 mL/mL), propylene glycol (0.1 mL/mL), at pH 6-7 is thenprepared in a 2 cc glass vial. The air in the vial is evacuated andreplaced with perfluoropropane and the vial is sealed. The ultrasoundcontrast agent composition is completed by agitating the sealed vial ina dental amalgamator for 30-45 sec. to form a milky white solution.

Example 65 Part A. Preparation of(ω-amino-PEG₃₄₀₀-α-carbonyl)-cyclo(Arg-Gly-Asp-D-Phe-Lys)

To a solution of N-Boc-ω-amino-PEG₃₄₀₀-α-carboxylate sucinimidyl ester(1 mmol) and cyclo(Arg-Gly-Asp-D-Phe-Lys) (1 mmol) in DMF (25 mL) isadded triethylamine (3 mmol). The reaction mixture is stirred undernitrogen at room temperature overnight and the solvent is removed invacuo. The crude product is dissolved in 50% trifluoroaceticacid/dichloromethane and is stirred for 4 h. The volatiles are removedand the title compound is isolated as the TFA salt via trituration indiethyl ether.

Part B. Preparation of1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-((ω-amino-PEG₃₄₀₀-α-carbonyl)-cyclo(Arg-Gly-Asp-D-Phe-Lys))-Dodecane-1,12-Dione

A solution of disuccinimidyl dodecanoate (1 mmol),1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (1 mmol) and(ω-amino-PEG₃₄₀₀-α-carbonyl)-cyclo(Arg-Gly-Asp-D-Phe-Lys)TFA salt (1mmol) in 25 ml chloroform is stirred for 5 min. Sodium carbonate (1mmol) and sodium sulfate (1 mmol) are added and the solution is stirredat room temperature under nitrogen for 18 h. DMF is removed in vacuo andthe crude product is purified to obtain the title compound.

Part C. Preparation of Contrast Agent Composition

The1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-((ω-amino-PEG₃₄₀₀-α-carbonyl)-cyclo(Arg-Gly-Asp-D-Phe-Lys))-Dodecane-1,12-Dioneis admixed with three other lipids,1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid,1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, andN-(methoxypolyethylene glycol 5000carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine inrelative amounts of 1 wt. %:6 wt. %:54 wt. %:41 wt. %. An aqueoussolution of this lipid admixture (1 mg/mL), sodium chloride (7 mg/mL),glycerin (0.1 mL/mL), propylene glycol (0.1 mL/mL), at pH 6-7 is thenprepared in a 2 cc glass vial. The air in the vial is evacuated andreplaced with perfluoropropane and the vial is sealed. The ultrasoundcontrast agent composition is completed by agitating the sealed vial ina dental amalgamator for 30-45 sec. to form a milky white solution.

Example 66 Part A. Preparation of Synthesis of(ω-amino-PEG₃₄₀₀-α-carbonyl)-Glu-(cyclo(Arg-Gly-Asp-D-Phe-Lys))₂

To a solution of N-Boc-ω-amino-PEG₃₄₀₀-α-carboxylate sucinimidyl ester(1 mmol) and Glu-(cyclo(Arg-Gly-Asp-D-Phe-Lys))₂ (1 mmol) in DMF (25 mL)is added triethylamine (3 mmol). The reaction mixture is stirred undernitrogen at room temperature overnight and the solvent is removed invacuo. The crude product is dissolved in 50% trifluoroaceticacid/dichloromethane and is stirred for 4 h. The volatiles are removedand the title compound is isolated as the TFA salt via trituration indiethyl ether.

Part B. Preparation of1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-((ω-amino-PEG₃₄₀₀-α-carbonyl)-Glu-(cyclo(Arg-Gly-Asp-D-Phe-Lys))₂)-Dodecane-1,12-Dione

A solution of disuccinimidyl dodecanoate (1 mmol),1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (1 mmol) and(ω-amino-PEG₃₄₀₀-α-carbonyl)-Glu-(cyclo(Arg-Gly-Asp-D-Phe-Lys))₂ TFAsalt (1 mmol) in 25 ml chloroform is stirred for 5 min. Sodium carbonate(1 mmol) and sodium sulfate (1 mmol) are added and the solution isstirred at room temperature under nitrogen for 18 h. DMF is removed invacuo and the crude product is purified to obtain the title compound.

Part C. Preparation of Contrast Agent Composition

The1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-((ω-amino-PEG₃₄₀₀-α-carbonyl)-Glu-(cyclo(Arg-Gly-Asp-D-Phe-Lys))₂)-Dodecane-1,12-Dioneis admixed with three other lipids,1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid,1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, andN-(methoxypolyethylene glycol 5000carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine inrelative amounts of 1 wt. %:6 wt. %:54 wt. %. An aqueous solution of thelipid admixture (1 mg/ml), sodium chloride (7 mg/ml), glycerin (0.1mL/mL), propylene glycol (0.1 mL/mL), at 6-7 is then prepared in a 2 ccglass vial. The air in the vial is evacuated and replaced withperfluoropropane and the vial is sealed. The ultrasound contrast agentcomposition is completed by agitating the sealed vial in a dentalamalgamator for 30-45 sec. to form a milky white solution.

Analytical Methods

HPLC Method 3

Column: Zorbax C18, 25 cm×4.6 mm or Vydac C18, 25 cm×4.6 mm

Column Temperature: ambient

Flow: 1.0 mL/min

Solvent A: 10 mM sodium phosphate buffer pH 6

Solvent B: 100% Acetonitrile

Detector: sodium iodide (NaI) radiometric probe or beta detector

Gradient A (Exs. 33, 51) t (min) 0 20 30 31 40 % B 0 75 75 0 0 GradientB (Exs. 39, 40, 43, 44, 45, 46, 48, 50) t (min) 0 20 30 31 35 36 40 % B0 25 25 75 75 0 0 Gradient C (Examples 34, 35, 36, 37, 38, 42): t (min)0 40 41 46 47 55 % B 0 35 75 75 0 0 Gradient D (Ex. 49) t (min) 0 20 3031 40 % B 0 25 25 0 0 Gradient E (Exs. 55, 56): t (min) 0 20 21 30 31 40% B 0 20 50 50 0 0 Gradient F (Exs. 57, 58): t (min) 0 15 16 25 26 35 %B 0 20 75 75 0 0 Gradient G (Ex. 59): t (min) 0 20 21 30 31 40 % B 0 2075 75 0 0 Gradient H (Exs. 60, 61, 62): t (min) 0 15 16 21 22 40 % B 020 50 50 0 0 Gradient I (Exs. 52, 53, 54) t (min) 0 20 21 30 31 40 %Solvent B 5 20 60 60 5 5 Gradient J (Ex. 41) t (min) 0 20 30 31 40 %Solvent B 0 50 50 0 0 Gradient K (Ex. 47) t (min) 0 20 21 30 31 40 %Solvent B 10 20 60 60 10 10

HPLC Method 4

Column: Zorbax C18, 25 cm×4.6 mm

Flow: 1.0 mL/min

Solvent A: 10 mM ammonium acetate

Solvent B: 100% methanol

Gradient: t (min) 0 23 26 27 % B 8 100 100 8

UV Detection

ITLC Method

Gelman ITLC-SG strips (2 cm×7.5 cm)

Solvent System: 1:1 acetone:saline

Detection using a Bioscan System 200.

UTILITY

The pharmaceuticals of the present invention are useful for imagingangiogenic tumor vasculature in a patient or for treating cancer in apatient. The radiopharmaceuticals of the present invention comprised ofa gamma emitting isotope are useful for imaging of pathologicalprocesses involving angiogenic neovasculature, including cancer,diabetic retinopathy, macular degeneration, restenosis of blood vesselsafter angioplasty, and wound healing. Diagnostic utilities also includeimaging of unstable coronary syndromes (e.g., unstable coronary plaque).The radiopharmaceuticals of the present invention comprised of a beta,alpha or Auger electron emitting isotope are useful for treatment ofpathological processes involving angiogenic neovasculature, bydelivering a cytotoxic dose of radiation to the locus of the angiogenicneovasculature. The treatment of cancer is affected by the systemicadministration of the radiopharmaceuticals resulting in a cytotoxicradiation dose to tumors.

The compounds of the present invention comprised of one or moreparamagnetic metal ions selected from gadolinium, dysprosium, iron, andmanganese, are useful as contrast agents for magnetic resonance imaging(MRI) of pathological processes involving angiogenic neovasculature.

The compounds of the present invention comprised of one or more heavyatoms with atmic number of 20 or greater are useful as X-ray contrastagents for X-ray imaging of pathological processes involving angiogenicneovasculature.

The compounds of the present invention comprised of an echogenic gascontaining surfactant microsphere are useful as ultrasound contrastagents for sonography of pathological processes involving angiogenicneovasculature.

Representative compounds of the present invention were tested in thefollowing in vitro and in vivo assays and models and were found to beactive.

Immobilized Human Placental α_(v)β₃ Receptor Assay

The assay conditions were developed and validated using[I-125]vitronectin. Assay validation included Scatchard format analysis(n=3) where receptor number (Bmax) and Kd (affinity) were determined.Assay format is such that compounds are preliminarily screened at 10 and100 nM final concentrations prior to IC50 determination. Three standards(vitronectin, anti-α_(v)β₃ antibody, LM609, and anti-α_(v)β₅, P1F6) andfive reference peptides have been evaluated for IC50 determination.Briefly, the method involves immobilizing previously isolated receptorsin 96 well plates and incubating overnight. The receptors were isolatedfrom normal, fresh, non-infectious (HIV, hepatitis B and C, syphilis,and HTLV free) human placenta. The tissue was lysed and tissue debrisremoved via centrifugation. The lysate was filtered. The receptors wereisolated by affinity chromatography using the immobilized α_(v)β₃antibody. The plates are then washed 3× with wash buffer. Blockingbuffer is added and plates incubated for 120 minutes at roomtemperature. During this time, compounds to be tested and[I-125]vitronectin are premixed in a reservoir plate. Blocking buffer isremoved and compound mixture pipetted. Competition is carried out for 60minutes at room temperature. Unbound material is then removed and wellsare separated and counted via gamma scintillation.

Other Receptor Binding Assays

Whole cell assays for the determination of the binding affinity ofpharmaceuticals of the present invention for the VEGF receptors,Flk-1/KDR and Flt-1, are described in Ortega, et. al., Amer. J. Pathol.,1997, 151, 1215-1224, and Dougher, et. al., Growth Factors, 1997, 14,257-268. An in vitro assay for determining the affinity ofpharmaceuticals of the present invention for the bFGF receptor isdescribed in Yayon, et. al., Proc. Natl. Acad. Sci USA, 1993, 90,10643-10647. Gho et. al., Cancer Research, 1997, 57, 3733-40, describeassays for angiogenin receptor binding peptides. Senger, et. al., Proc.Natl. Acad. Sci USA, 1997, 94, 13612-13617 describe assays forantagonists of the integrins a1B1 and a2B1. U.S. Pat. No. 5,536,814describes assays for compounds that bind to the integrin a5B1.

Oncomouse® Imaging

The study involves the use of the c-Neu Oncomouse® and FVB micesimultaneously as controls. The mice are anesthetized with sodiumpentobarbital and injected with approximately 0.5 mCi ofradiopharmaceutical. Prior to injection, the tumor locations on eachOncomouse® are recorded and tumor size measured using calipers. Theanimals are positioned on the camera head so as to image the anterior orposterior of the animals. 5 Minute dynamic images are acquired seriallyover 2 hours using a 256×256 matrix and a zoom of 2×. Upon completion ofthe study, the images are evaluated by circumscribing the tumor as thetarget region of interest (ROI) and a background site in the neck areabelow the carotid salivary glands.

This model can also be used to assess the effectiveness of theradiopharmaceuticals of the present invention comprised of a beta, alphaor Auger electron emitting isotope. The radiopharmaceuticals areadministered in appropriate amounts and the uptake in the tumors can bequantified either non-invasively by imaging for those isotopes with acoincident imageable gamma emission, or by excision of the tumors andcounting the amount of radioactivity present by standard techniques. Thetherapeutic effect of the radiopharmaceuticals can be assessed bymonitoring the rate of growth of the tumors in control mice versus thosein the mice administered the radiopharmaceuticals of the presentinvention.

This model can also be used to assess the compounds of the presentinvention comprised of paramagnetic metals as MRI contrast agents. Afteradministration of the appropriate amount of the paramagnetic compounds,the whole animal can be placed in a commercially available magneticresonance imager to image the tumors. The effectiveness of the contrastagents can be readily seen by comparison to the images obtain fromanimals that are not administered a contrast agent.

This model can also be used to assess the compounds of the presentinvention comprised of heavy atoms as X-ray contrast agents. Afteradministration of the appropriate amount of the X-ray absorbingcompounds, the whole animal can be placed in a commercially availableX-ray imager to image the tumors. The effectiveness of the contrastagents can be readily seen by comparison to the images obtain fromanimals that are not administered a contrast agent.

This model can also be used to assess the compounds of the presentinvention comprised of an echogenic gas containing surfactantmicrosphere as ultrasound contrast agents. After administration of theappropriate amount of the echogenic compounds, the tumors in the animalcan be imaging using an ultrasound probe held proximate to the tumors.The effectiveness of the contrast agents can be readily seen bycomparison to the images obtain from animals that are not administered acontrast agent.

Rabbit Matrigel Model

This model was adapted from a matrigel model intended for the study ofangiogenesis in mice. Matrigel (Becton & Dickinson, USA) is a basementmembrane rich in laminin, collagen IV, entactin, HSPG and other growthfactors. When combined with growth factors such as bFGF [500 ng/ml] orVEGF [2 μg/ml] and injected subcutaneously into the mid-abdominal regionof the mice, it solidifies into a gel and stimulates angiogenesis at thesite of injection within 4-8 days. In the rabbit model, New ZealandWhite rabbits (2.5-3.0 kg) are injected with 2.0 ml of matrigel, plus 1μg bFGF and 4 μg VEGF. The radiopharmaceutical is then injected 7 dayslater and the images obtained.

This model can also be used to assess the effectiveness of theradiopharmaceuticals of the present invention comprised of a beta, alphaor Auger electron emitting isotope. The radiopharmaceuticals areadministered in appropriate amounts and the uptake at the angiogenicsites can be quantified either non-invasively by imaging for thoseisotopes with a coincident imageable gamma emission, or by excision ofthe angiogenic sites and counting the amount of radioactivity present bystandard techniques. The therapeutic effect of the radiopharmaceuticalscan be assessed by monitoring the rate of growth of the angiogenic sitesin control rabbits versus those in the rabbits administered theradiopharmaceuticals of the present invention.

This model can also be used to assess the compounds of the presentinvention comprised of paramagnetic metals as MRI contrast agents. Afteradministration of the appropriate amount of the paramagnetic compounds,the whole animal can be placed in a commercially available magneticresonance imager to image the angiogenic sites. The effectiveness of thecontrast agents can be readily seen by comparison to the images obtainfrom animals that are not administered a contrast agent.

This model can also be used to assess the compounds of the presentinvention comprised of heavy atoms as X-ray contrast agents. Afteradministration of the appropriate amount of the X-ray absorbingcompounds, the whole animal can be placed in a commercially availableX-ray imager to image the angiogenic sites. The effectiveness of thecontrast agents can be readily seen by comparison to the images obtainfrom animals that are not administered a contrast agent.

This model can also be used to assess the compounds of the presentinvention comprised of an echogenic gas containing surfactantmicrosphere as ultrasound contrast agents. After administration of theappropriate amount of the echogenic compounds, the angiogenic sites inthe animal can be imaging using an ultrasound probe held proximate tothe tumors. The effectiveness of the contrast agents can be readily seenby comparison to the images obtain from animals that are notadministered a contrast agent.

Canine Spontaneous Tumor Model

Adult dogs with spontaneous mammary tumors were sedated with xylazine(20 mg/kg)/atropine (1 ml/kg). Upon sedation the animals were intubatedusing ketamine (5 mg/kg)/diazepam (0.25 mg/kg) for full anethesia.Chemical restraint was continued with ketamine (3 mg/kg)/xylazine (6mg/kg) titrating as necessary. If required the animals were ventilatedwith room air via an endotrachael tube (12 strokes/min, 25 ml/kg) duringthe study. Peripheral veins were catheterized using 20G I.V. catheters,one to serve as an infusion port for compound while the other forexfusion of blood samples. Heart rate and EKG were monitored using acardiotachometer (Biotech, Grass Quincy, Mass.) triggered from a lead IIelectrocardiogram generated by limb leads. Blood samples are generallytaken at ˜10 minutes (control), end of infusion, (1 minute), 15 min, 30min, 60 min, 90 min, and 120 min for whole blood cell number andcounting. Radiopharmaceutical dose was 300 μCi/kg adminitered as an i.v.bolus with saline flush. Parameters were monitored continuously on apolygraph recorder (Model 7E Grass) at a paper speed of 10 mm/min or 10mm/sec.

Imaging of the laterals were for 2 hours with a 256×256 matrix, no zoom,5 minute dynamic images. A known source is placed in the image field(20-90 μCi) to evaluate region of interest (ROI) uptake. Images werealso acquired 24 hours post injection to determine retention of thecompound in the tumor. The uptake is determined by taking the fractionof the total counts in an inscribed area for ROI/source and multiplyingthe known μCi. The result is μCi for the ROI.

This model can also be used to assess the effectiveness of theradiopharmaceuticals of the present invention comprised of a beta, alphaor Auger electron emitting isotope. The radiopharmaceuticals areadministered in appropriate amounts and the uptake in the tumors can bequantified either non-invasively by imaging for those isotopes with acoincident imageable gamma emission, or by excision of the tumors andcounting the amount of radioactivity present by standard techniques. Thetherapeutic effect of the radiopharmaceuticals can be assessed bymonitoring the size of the tumors over time.

This model can also be used to assess the compounds of the presentinvention comprised of paramagnetic metals as MRI contrast agents. Afteradministration of the appropriate amount of the paramagnetic compounds,the whole animal can be placed in a commercially available magneticresonance imager to image the tumors. The effectiveness of the contrastagents can be readily seen by comparison to the images obtain fromanimals that are not administered a contrast agent.

This model can also be used to assess the compounds of the presentinvention comprised of heavy atoms as X-ray contrast agents. Afteradministration of the appropriate amount of the X-ray absorbingcompounds, the whole animal can be placed in a commercially availableX-ray imager to image the tumors. The effectiveness of the contrastagents can be readily seen by comparison to the images obtain fromanimals that are not administered a contrast agent.

This model can also be used to assess the compounds of the presentinvention comprised of an echogenic gas containing surfactantmicrosphere as ultrasound contrast agents. After administration of theappropriate amount of the echogenic compounds, the tumors in the animalcan be imaging using an ultrasound probe held proximate to the tumors.The effectiveness of the contrast agents can be readily seen bycomparison to the images obtain from animals that are not administered acontrast agent.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein. 056955731

What is claimed is:
 1. A kit for treating cancer, comprising a compound,comprising: a) a targeting moiety; b) a chelator; and c) 0-1 linkinggroups between the targeting moiety and chelator; wherein the targetingmoiety is a peptide or peptidomimetic, and binds to a α_(v)β₃ receptorthat is upregulated during angiogenesis, or a pharmaceuticallyacceptable salt thereof, and at least one agent selected from the groupconsisting of a chemotherapeutic agent and a radiosensitizer agent, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 2. A kit according to claim 1 wherein said kitcomprises a plurality of separate containers, wherein at least one ofsaid containers contains said compound, or a pharmaceutically acceptablesalt thereof, and at least another of said containers contains one ormore agents selected from the group consisting of a chemotherapeuticagent and a radiosensitizer agent, or a pharmaceutically acceptable saltthereof, and pharmaceutically acceptable carrier.
 3. A kit according toclaim 1, wherein the chemotherapeutic agent is selected from the groupconsisting of mitomycin, tretinoin, ribomustin, gemcitabine,vincristine, etoposide, cladribine, mitobronitol, methotrexate,doxorubicin, carboquone, pentostatin, nitracrine, zinostatin,cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole,fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine,bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine,proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate,isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil,butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol,tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide,improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen,progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha,interferon-2 alpha, interferon-beta, interferon-gamma, colonystimulating factor-1, colony stimulating factor-2, denileukin diftitox,interleukin-2, and leutinizing hormone releasing factor.
 4. A kitaccording to claim 1, wherein the chemotherapeutic agent is selectedfrom the group consisting of mitomycin, tretinoin, ribomustin,gemcitabine, vincristine, etoposide, cladribine, mitobronitol,methotrexate, doxorubicin, carboquone, pentostatin, nitracrine,zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole,fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine,bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine,proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate,isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil,butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol,tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide,improsulfan, enocitabine, and lisuride.
 5. A kit according to claim 1,wherein the chemotherapeutic agent is selected from the group consistingof oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol,and formestane.
 6. A kit according to claim 1 wherein thechemotherapeutic agent is selected from the group consisting ofinterferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma,colony stimulating factor-1, colony stimulating factor-2, denileukindiftitox, interleukin-2, and leutinizing hormone releasing factor.
 7. Akit according to claim 1, wherein radiosensitizer agent is selected fromthe group consiting of2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide,N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine,3-amino-1,2,4-benzotriazine-1,4-dioxide,N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide,1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol.
 8. A therapeuticradiopharmaceutical composition comprising: a metal, and a compoundwherein the compound comprises: a) a chelator capable of chelating themetal; b) a targeting moiety; and c) 0-1 linking groups between thetargeting moiety and chelator; wherein the targeting moiety is a peptideor peptidomimetic, and binds to α_(v)β₃ receptor that is upregulatedduring angiogenesis, and wherein the composition further comprising atleast one agent selected from the group consisting of a chemotherapeuticagent and a radiosensitizer agent, or a pharmaceutically acceptable saltthereof.
 9. A therapeutic radiopharmaceutical composition according toclaim 8, wherein the chemotherapeutic agent is selected from the groupconsisting of mitomycin, tretinoin, ribomustin, gemcitabine,vincristine, etoposide, cladribine, mitobronitol, methotrexate,doxorubicin, carboquone, pentostatin, nitracrine, zinostatin,cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole,fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine,bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine,proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate,isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil,butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol,tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide,improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen,progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha,interferon-2 alpha, interferon-beta, interferon-gamma, colonystimulating factor-1, colony stimulating factor-2, denileukin diftitox,interleukin-2, and leutinizing hormone releasing factor.
 10. Atherapeutic radiopharmaceutical composition according to claim 8,wherein radiosensitizer agent is selected from the group consisting of2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide,N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine,3-amino-1,2,4-benzotriazine-1,4-dioxide,N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide,1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol.
 11. A method oftreating cancer in a patient comprising: administering to a patient inneed thereof a therapeutic radiopharmaceutical or a pharmaceuticallyacceptable salt thereof, and at least one agent selected from the groupconsisting of a chemotherapeutic agent and a radiosensitizer agent, or apharmaceutically acceptable salt thereof, wherein the therapeuticradiopharmaceutical comprises a metal and a compound, wherein thecompound comprises: a) a chelator capable of chelating the metal; b) atargeting moiety; and c) 0-1 linking groups between the targeting moietyand chelator; wherein the targeting moiety is a peptide orpeptidomimetic, and binds to a α_(v)β₃ receptor that is upregulatedduring angiogenesis; and wherein the metal is a radioisotope selectedfrom the group: ³³P, ¹²⁵I, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, 149pm,⁹⁰Y, ²¹²Bi, ¹⁰³Pd, ¹⁰⁹Pd, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁶⁹Yb, ¹⁷⁵Yb,¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, ¹⁰⁵Rh, ¹¹¹Ag, and ¹⁹²Ir.
 12. A method of treatingcancer according to claim 11, wherein the administration is by injectionor infusion.
 13. A method according to claim 11 wherein administeringthe therapeutic radiopharmaceutical and agent is concurrent.
 14. Amethod according to claim 11 wherein administering the therapeuticradiopharmaceutical and agent is sequential.
 15. A method according toclaim 11 wherein the cancer is selected from the group consisting ofcarcinomas of the lung, breast, ovary, stomach, pancreas, larynx,esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix,uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cellcarcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas,and neuroblastomas.
 16. A method according to claim 11 wherein thechemotherapeutic agent is selected from the group consisting ofmitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide,cladribine, mitobronitol, methotrexate, doxorubicin, carboquone,pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed,daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane,nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone,aminoglutethimide, amsacrine, proglumide, elliptinium acetate,ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin,nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane,sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine,picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride,oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol,formestane, interferon-alpha, interferon-2 alpha, interferon-beta,interferon-gamma, colony stimulating factor-1, colony stimulatingfactor-2, denileukin diftitox, interleukin-2, and leutinizing hormonereleasing factor.
 17. A method according to claim 11 wherein theradiosensitizer agent is selected from the group consiting of2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide,N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine,3-amino-1,2,4-benzotriazine-1,4-dioxide,N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide,1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol.
 18. A kit accordingto claim 1, wherein the linking group is present between the targetingmoiety and chelator.
 19. A kit according to claim 18, wherein compoundis of the formula: (Q)_(d)—L_(n)—C_(h) or (Q)_(d)—L_(n)—(C_(h))_(d′)wherein, Q is a peptide independently selected from the group:

K is an L-amino acid independently selected at each occurrence from thegroup: arginine, citrulline, N-methylarginine, lysine, homolysine,2-aminoethylcysteine, δ-N-2-imidazolinylornithine,δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid; K is a D-amino acidindependently selected at each occurrence from the group: arginine,citrulline, N-methylarginine, lysine, homolysine, 2-aminoethylcysteine,δ-N-2-imidazolinylornithine, δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid; L is independentlyselected at each occurrence from the group: glycine, L-alanine, andD-alanine; M is L-aspartic acid; M′ is D-aspartic acid; R¹ is an aminoacid substituted with 0-1 bonds to L_(n), independently selected at eachoccurrence from the group: glycine, L-valine, D-valine, alanine,leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoicacid, tyrosine, phenylalanine, thienylalanine, phenylglycine,cyclohexylalanine, homophenylalanine, 1-naphthylalanine, lysine, serine,ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine,penicillamine, and methionine; R² is an amino acid, substituted with 0-1bonds to L_(n), independently selected at each occurrence from thegroup: glycine, valine, alanine, leucine, isoleucine, norleucine,2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, L-phenylalanine,D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine,cyclohexylalanine, homophenylalanine, L-1-naphthylalanine,D-1-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid,1,2-diaminopropionic acid, cysteine, penicillamine, methionine, and2-aminothiazole-4-acetic acid; R³ is an amino acid, substituted with 0-1bonds to L_(n), independently selected at each occurrence from thegroup: glycine, D-valine, D-alanine, D-leucine, D-isoleucine,D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine,D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine,D-homophenylalanine, D-1-naphthylalanine, D-lysine, D-serine,D-ornithine, D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid,D-cysteine, D-penicillamine, and D-methionine; R⁴ is an amino acid,substituted with 0-1 bonds to L_(n), independently selected at eachoccurrence from the group: glycine, D-valine, D-alanine, D-leucine,D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoicacid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine,D-cyclohexylalanine, D-homophenylalanine, D-1-naphthylalanine, D-lysine,D-serine, D-ornithine, D-1,2-diaminobutyric acid, D-1,2-diaminopropionicacid, D-cysteine, D-penicillamine, D-methionine, and2-aminothiazole-4-acetic acid; R⁵ is an amino acid, substituted with 0-1bonds to L_(n), independently selected at each occurrence from thegroup: glycine, L-valine, L-alanine, L-leucine, L-isoleucine,L-norleucine, L-2-aminobutyric acid, L-2-aminohexanoic acid, L-tyrosine,L-phenylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine,L-homophenylalanine, L-1-naphthylalanine, L-lysine, L-serine,L-ornithine, L-1,2-diaminobutyric acid, L-1,2-diaminopropionic acid,L-cysteine, L-penicillamine, L-methionine, and 2-aminothiazole-4-aceticacid; provided that one of R¹, R², R³, R⁴, and R⁵ in each Q issubstituted with a bond to L_(n), further provided that when R² is2-aminothiazole-4-acetic acid, K is N-methylarginine, further providedthat when R⁴ is 2-aminothiazole-4-acetic acid, K and K′ areN-methylarginine, and still further provided that when R⁵ is2-aminothiazole-4-acetic acid, K′ is N-methylarginine; d is selectedfrom 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; L_(n) is a linking group havingthe formula:(CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)—(Z)_(k)—(W)_(h′)(CR⁸R⁹)_(g″)—(W)_(h″)—(CR^(8a)R^(9a))_(g″′) provided that g+h+g′+k+h′+g″+h″+g″′ is other than 0; W is independentlyselected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH,C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, (OCH₂CH₂)_(s),(CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), (CH₂CH₂CH₂O)_(t), and (aa)_(t″); aais independently at each occurrence an amino acid; Z is selected fromthe group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀ cycloalkyl substitutedwith 0-3 R¹⁰, and a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O and substitutedwith 0-3 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹ and R^(9a) areindependently selected at each occurrence from the group: H, ═O, COOH,SO₃H, PO₃H, C₁-C₅ alkyl substituted with 0-3 R¹⁰, aryl substituted with0-3 R¹⁰, benzyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substitutedwith 0-3 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and abond to C_(h); R¹⁰ is independently selected at each occurrence from thegroup: a bond to C_(h), COOR¹¹, OH, NHR¹¹, SO₃H, PO₃H, aryl substitutedwith 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxysubstituted with 0-1 R¹², and a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-3 R¹¹; R¹¹ is independently selected at eachoccurrence from the group: H, aryl substituted with 0-1 R¹², a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-1 R¹²,C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycolsubstituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹²,cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substitutedwith 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide iscomprised of 2-10 amino acids, and a bond to C_(h); R¹² is a bond toC_(h); k is selected from 0, 1, and 2; h is selected from 0, 1, and 2;h′ is selected from 0, 1, 2, 3, 4, and 5; h″ is selected from 0, 1, 2,3, 4, and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g′is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″ is selectedfrom 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″′ is selected from 0, 1, 2,3, 4, 5, 6, 7, 8, 9, and 10; s is selected from 0, 1, 2, 3, 4, 5, 6, 7,8, 9, and 10; s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is selectedfrom 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t′ is selected from 0, 1, 2,3, 4, 5, 6, 7, 8, 9, and 10; C_(h) is a metal bonding unit having aformula selected from the group:

A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at eachoccurrence from the group N, NR¹³, NR¹³R¹⁴, S, SH, S(Pg), O, OH, PR¹³,PR¹³R¹⁴, P(O)R¹⁵R¹⁶, and a bond to L_(n); E is a bond, CH, or a spacergroup independently selected at each occurrence from the group: C₁-C₁₀alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substitutedwith 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷;R¹³, and R¹⁴ are each independently selected from the group: a bond toL_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substitutedwith 0-3 R¹⁷, C₁₋₁₀ cycloalkyl substituted with 0-3 R¹⁷,heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷; wherein theheterocyclo group is a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀aryl-substituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring systemcontaining 14 heteroatoms independently selected from N, S, and O andsubstituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³or R¹⁴ is an electron, then the other is also an electron;alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹); R¹⁵ and R¹⁶ areeach independently selected from the group: a bond to L_(n), —OH, C₁-C₁₀alkyl substituted with 0-3 R¹⁷, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷,aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein theheterocyclo group is a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ringsystem containing 1-4 heteroatoms independently selected from N, S, andO and substituted with 0-3 R¹⁷; R¹⁷ is independently selected at eachoccurrence from the group: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN,—CO₂R¹⁸, —C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CHO, —CH₂OR¹⁸, —OC(═O)R¹⁸,—OC(═O)OR^(18a), —OR¹⁸, —OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸,—NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂, —NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a),—SO₃H, —SO₂R^(18a), —SR¹⁸, —S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂,—NHC(═S)NHR¹⁸, ═NOR¹⁸, NO₂, —C(═O)NHOR¹⁸, —C(═O)NHNR¹⁸R^(18a),—OCH₂CO₂H, 2-(1-morpholino)ethoxy, C₁-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkylmethyl, C₂-C₆ alkoxyalkyl, aryl substitutedwith 0-2 R¹⁸, and a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O; R¹⁸, R^(18a),and R¹⁹ are independently selected at each occurrence from the group: abond to L_(n), H, C₁-C₆ alkyl, phenyl, benzyl, C₁-C₆ alkoxy, halide,nitro, cyano, and trifluoromethyl; Pg is a thiol protecting group; R²⁰and R²¹ are independently selected from the group: H, C₁-C₁₀ alkyl, —CN,—CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, C₂-C₁₀ 1-alkene substituted with 0-3R²³, C₂-C₁₀ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3R²³, unsaturated 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-3 R²³, and unsaturated C₃₋₁₀ carbocycle substituted with 0-3 R²³;alternatively, R²⁰ and R²¹, taken together with the divalent carbonradical to which they are attached form:

R²² and R²³ are independently selected from the group: H, R²⁴, C₁-C₁₀alkyl substituted with 0-3 R²⁴, C₂-C₁₀ alkenyl substituted with 0-3 R²⁴,C₂-C₁₀ alkynyl substituted with 0-3 R²⁴, aryl substituted with 0-3 R²⁴,a 5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R²⁴,and C₃₋₁₀ carbocycle substituted with 0-3 R²⁴; alternatively, R²², R²³taken together form a fused aromatic or a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O; a and b indicate the positions of optional double bonds and n is0 or 1; R²⁴ is independently selected at each occurrence from the group:═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, —N(R²⁵)₃⁺, —CH₂OR²⁵, —OC(═O)R²⁵, —OC(═O)OR^(25a), —OR²⁵, —OC(═O)N(R²⁵)₂,—NR²⁶C(═O)R²⁵, —NR²⁶C(═O)OR^(25a), —NR²⁶C(═O)N(R²⁵)₂, —NR²⁶SO₂N(R²⁵)₂,—NR²⁶SO₂R^(25a), —SO₃H, —SO₂R^(25a), —SR²⁵, —S(═O)R^(25a), —SO₂N(R²⁵)₂,—N(R²⁵)₂, ═NOR²⁵, —C(═O)NHOR²⁵, —OCH₂CO₂H, and 2-(1-morpholino)ethoxy;and, R²⁵, R^(25a), and R²⁶ are each independently selected at eachoccurrence from the group: hydrogen and C₁-C₆ alkyl; and apharmaceutically acceptable salt thereof.
 20. A kit according to claim19, wherein L is glycine; R¹ is an amino acid, optionally substitutedwith a bond to L_(n), independently selected at each occurrence from thegroup: L-valine, D-valine, alanine, leucine, isoleucine, norleucine,2-aminobutyric acid, tyrosine, phenylalanine, phenylglycine,cyclohexylalanine, homophenylalanine, lysine, ornithine,1,2-diaminobutyric acid, and 1,2-diaminopropionic acid; R² is an aminoacid, optionally substituted with a bond to L_(n), independentlyselected at each occurrence from the group: valine, alanine, leucine,isoleucine, norleucine, 2-aminobutyric acid, tyrosine, L-phenylalanine,D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine,cyclohexylalanine, homophenylalanine, L-1-naphthylalanine,D-1-naphthylalanine, lysine, ornithine, 1,2-diaminobutyric acid,1,2-diaminopropionic acid, and 2-aminothiazole-4-acetic acid; R³ is anamino acid, optionally substituted with a bond to L_(n), independentlyselected at each occurrence from the group: D-valine, D-alanine,D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-tyrosine, D-phenylalanine, D-phenylglycine, D-cyclohexylalanine,D-homophenylalanine, D-lysine, D-serine, D-ornithine,D-1,2-diaminobutyric acid, and D-1,2-diaminopropionic acid; R⁴ is anamino acid, optionally substituted with a bond to L_(n), independentlyselected at each occurrence from the group: D-valine, D-alanine,D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine,D-cyclohexylalanine, D-homophenylalanine, D-1-naphthylalanine, D-lysine,D-ornithine, D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid, and2-aminothiazole-4-acetic acid; R⁵ is an amino acid, optionallysubstituted with a bond to L_(n), independently selected at eachoccurrence from the group: L-valine, L-alanine, L-leucine, L-isoleucine,L-norleucine, L-2-aminobutyric acid, L-tyrosine, L-phenylalanine,L-thienylalanine, L-phenylglycine, L-cyclohexylalanine,L-homophenylalanine, L-1-naphthylalanine, L-lysine, L-ornithine,L-1,2-diaminobutyric acid, L-1,2-diaminopropionic acid, and2-aminothiazole-4-acetic acid; d is selected from 1, 2, and 3; W isindependently selected at each occurrence from the group: O, NH,NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂,(OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), and (CH₂CH₂CH₂O)_(t),Z is selected from the group: aryl substituted with 0-1 R¹⁰, C₃₋₁₀cycloalkyl substituted with 0-1 R¹⁰, and a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O and substituted with 0-1 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a),R⁹, and R^(9a) are independently selected at each occurrence from thegroup: H, ═O, COOH, SO₃H, C₁-C₅ alkyl substituted with 0-1 R¹⁰, arylsubstituted with 0-1 R¹⁰, benzyl substituted with 0-1R¹⁰, and C₁-C₅alkoxy substituted with 0-1R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹,NHR¹¹, R¹¹, and a bond to C_(h); R¹⁰ is independently selected at eachoccurrence from the group: COOR¹¹, OH, NHR¹¹, SO₃H, aryl substitutedwith 0-1 R¹¹, a 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-1 R¹¹, C₁-C₅ alkyl substituted with 0-1 R¹², C₁-C₅ alkoxy substitutedwith 0-1 R¹², and a bond to C_(h); R¹¹ is independently selected at eachoccurrence from the group: H, aryl substituted with 0-1 R¹², a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-1 R¹²,polyalkylene glycol substituted with 0-1 R¹², carbohydrate substitutedwith 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acidsubstituted with 0-1 R¹², and a bond to C_(h); k is 0 or 1; h is 0 or 1;h′ is 0or 1; s is selected from 0, 1, 2, 3, 4, and 5; s′ is selectedfrom 0, 1, 2, 3, 4, and 5; s″ is selected from 0, 1, 2, 3, 4, and 5; tis selected from 0, 1, 2, 3, 4, and 5; A¹, A², A³, A⁴, A⁵, A⁶, A⁷, andA⁸ are independently selected at each occurrence from the group: NR¹³,NR¹³R¹⁴, S, SH, S(Pg), OH, and a bond to L_(n); E is a bond, CH, or aspacer group independently selected at each occurrence from the group:C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷,C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-3 R¹⁷; R¹³, and R¹⁴ areeach independently selected from the group: a bond to L_(n), hydrogen,C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, a5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷,and an electron, provided that when one of R¹³ or R¹⁴ is an electron,then the other is also an electron; alternatively, R¹³ and R¹⁴ combineto form ═C(R²⁰)(R²¹); R¹⁷ is independently selected at each occurrencefrom the group: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸,—C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸,—OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂,—NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —S(═O)R^(18a),—SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR₁₈, ═NOR¹⁸, —C(═O)NHNR¹⁸R^(18a),—OCH₂CO₂H, and 2-(1-morpholino)ethoxy; R¹⁸, R^(18a), and R¹⁹ areindependently selected at each occurrence from the group: a bond toL_(n), H, and C₁-C₆ alkyl; R²⁰ and R²¹ are independently selected fromthe group: H, C₁-C₅ alkyl, —CO₂R²⁵, C₂-C₅ 1-alkene substituted with 0-3R²³, C₂-C₅ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3R²³, and unsaturated 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O and substitutedwith 0-3 R²³; alternatively, R²⁰ and R²¹, taken together with thedivalent carbon radical to which they are attached form:

R²² and R²³ are independently selected from the group: H, and R²⁴;alternatively, R²², R²³ taken together form a fused aromatic or a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O; R²⁴ is independently selectedat each occurrence from the group: —CO₂R²⁵, —C(═O)N(R²⁵)₂, —CH₂OR²⁵,—OC(═O)R²⁵, —OR²⁵, —SO₃H, —N(R²⁵)₂, and —OCH₂CO₂H; and, R²⁵ isindependently selected at each occurrence from the group: H and C₁-C₃alkyl.
 21. A kit according to claim 20, wherein: Q is a peptide selectedfrom the group:

R¹ is L-valine, D-valine, D-lysine optionally substituted on the ε aminogroup with a bond to L_(n) or L-lysine optionally substituted on the εamino group with a bond to L_(n); R² is L-phenylalanine,D-phenylalanine, D-1-naphthylalanine, 2-aminothiazole-4-acetic acid,L-lysine optionally substituted on the ε amino group with a bond toL_(n) or tyrosine, the tyrosine optionally substituted on the hydroxygroup with a bond to L_(n); R³ is D-valine, D-phenylalanine, or L-lysineoptionally substituted on the ε amino group with a bond to L_(n); R⁴ isD-phenylalanine, D-tyrosine substituted on the hydroxy group with a bondto L_(n), or L-lysine optionally substituted on the ε amino group with abond to L_(n); provided that one of R¹ and R² in each Q is substitutedwith a bond to L_(n), and further provided that when R² is2-aminothiazole-4-acetic acid, K is N-methylarginine; d is 1 or 2; W isindependently selected at each occurrence from the group: NHC(═O),C(═O)NH, C(═O), (CH₂CH₂O)_(s′), and (CH₂CH₂CH₂O)_(t); R⁶, R^(6a), R⁷,R^(7a), R⁸, R^(8a), R⁹, and R^(9a) are independently selected at eachoccurrence from the group: H, NHC(═O)R¹¹, and a bond to C_(h); k is 0;h″ is selected from 0, 1, 2, and 3; g is selected from 0, 1, 2, 3, 4,and 5; g′ is selected from 0, 1, 2, 3, 4, and 5; g″ is selected from 0,1, 2, 3, 4, and 5; g″′ is selected from 0, 1, 2, 3, 4, and 5; s′ is 1 or2; t is 1 or 2; C_(h) is

A¹ is selected from the group: OH, and a bond to L_(n); A², A⁴, and A⁶are each N; A³, A⁵, and A⁸ are each OH; A⁷ is a bond to L_(n) or NH-bondto L_(n); E is a C₂ alkyl substituted with 0-1 R¹⁷; R¹⁷ is ═O;alternatively, C_(h) is

A¹ is NH₂ or N═C(R²⁰)(R²¹); E is a bond; A² is NHR¹³; R¹³ is aheterocycle substituted with R¹⁷, the heterocycle being selected frompyridine and pyrimidine; R¹⁷ is selected from a bond to L_(n),C(═O)NHR¹⁸, and C(═O)R¹⁸; R¹⁸ is a bond to L_(n); R²⁴ is selected fromthe group: —CO₂R²⁵, —OR²⁵, —SO₃H, and —N(R²⁵)₂; R²⁵ is independentlyselected at each occurrence from the group: hydrogen and methyl;

 alternatively, C_(h) is A¹, A², A³, and A⁴ are each N; A⁵, A⁶, and A⁸are each OH; A⁷ is a bond to L_(n); E is a C₂ alkyl substituted with 0-1R¹⁷; and, R¹⁷ is ═O.
 22. A kit according to claim 20, wherein thecompound is selected from the group consisting of: (a)cyclo{Arg-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val }; (b)cyclo{Arg-Gly-Asp-D-Tyr((N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-18-amino-14-aza-4,7,10-oxy-15-oxo-octadecoyl)-3-aminopropyl)-Val};(c) [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp})-cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp};(d)cyclo{Arg-Gly-Asp-D-Tyr-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (e)cyclo{Arg-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (f)[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}; (g)[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Phe-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};(h)cyclo{Arg-Gly-Asp-D-Nal-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (i)[2-[[[5-[carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{(Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal};(j)cyclo{Arg-Gly-Asp-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Val}; (k)[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-D-Val-Arg-Gly-Asp})-cyclo{Lys-D-Val-Arg-Gly-Asp};(l){cyclo(Arg-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; (m)cyclo{D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Phe-D-Asp-Gly-Arg}; (n)[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg};(o)cyclo{D-Phe-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Asp-Gly-Arg}; (p)cyclo{N-Me-Arg-Gly-Asp-ATA-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (q)cyclo{Cit-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (r)2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};(s) cyclo{Arg-Gly-Asp-D-Phe-Lys(DTPA)}; (t)cyclo{Arg-Gly-Asp-D-Phe-Lys}₂(DTPA); (u)cyclo{Arg-Gly-Asp-D-Tyr(N-DTPA-3-aminopropyl)-Val}; (v)cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (w)cyclo{Lys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (x)cyclo{Cys(2-aminoethyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (y)cyclo{HomoLys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (z)cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (aa)cyclo{Dap(b-(2-benzimidazolylacetyl))-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (bb)cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (cc)cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (dd)cyclo{Lys-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; (ee)cyclo{Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; and, (ff)cyclo{Orn(d-N-2-Imidazolinyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; or a pharmaceutically acceptable saltform thereof.
 23. A kit according to claim 20, wherein the kit furthercomprises one or more ancillary ligands and a reducing agent.
 24. A kitaccording to claim 23, wherein the ancillary ligands are tricine andTPPTS.
 25. A kit according to claim 24, wherein the reducing agent istin(II).
 26. A therapeutic radiopharmaceutical composition according toclaim 8, wherein the metal is a radioisotope selected from the group:³³P, ¹²⁵I, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁰³Pd,¹⁰⁹Pd, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁶⁹ Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu,¹⁰⁵Rh, ¹¹¹ Ag, and ¹⁹²Ir.
 27. A therapeutic radiopharmaceuticalcomposition according to claim 26, wherein the compound is of theformula: (Q)_(d)—L_(n)—C_(h) or (Q)_(d)—L_(n)—(C_(h))_(d′) wherein, Q isa peptide independently selected from the group:

K is an L-amino acid independently selected at each occurrence from thegroup: arginine, citrulline, N-methylarginine, lysine, homolysine,2-aminoethylcysteine, δ-2-imidazolinylornithine,δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid; K′ is a D-amino acidindependently selected at each occurrence from the group: arginine,citrulline, N-methylarginine, lysine, homolysine, 2-aminoethylcysteine,δ-N-2-imidazolinylornithine, δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid; L is independentlyselected at each occurrence from the group: glycine, L-alanine, andD-alanine; M is L-aspartic acid; M′ is D-aspartic acid; R¹ is an aminoacid substituted with 0-1 bonds to L_(n), independently selected at eachoccurrence from the group: glycine, L-valine, D-valine, alanine,leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoicacid, tyrosine, phenylalanine, thienylalanine, phenylglycine,cyclohexylalanine, homophenylalanine, 1-naphthylalanine, lysine, serine,ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine,penicillamine, and methionine; R² is an amino acid, substituted with 0-1bonds to L_(n), independently selected at each occurrence from thegroup: glycine, valine, alanine, leucine, isoleucine, norleucine,2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, L-phenylalanine,D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine,cyclohexylalanine, homophenylalanine, L-1-naphthylalanine,D-1-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid,1,2-diaminopropionic acid, cysteine, penicillamine, methionine, and2-aminothiazole-4-acetic acid; R³ is an amino acid, substituted with 0-1bonds to L_(n), independently selected at each occurrence from thegroup: glycine, D-valine, D-alanine, D-leucine, D-isoleucine,D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine,D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine,D-homophenylalanine, D-1-naphthylalanine, D-lysine, D-serine,D-ornithine, D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid,D-cysteine, D-penicillamine, and D-methionine; R⁴ is an amino acid,substituted with 0-1 bonds to L_(n), independently selected at eachoccurrence from the group: glycine, D-valine, D-alanine, D-leucine,D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoicacid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine,D-cyclohexylalanine, D-homophenylalanine, D-1-naphthylalanine, D-lysine,D-serine, D-ornithine, D-1,2-diaminobutyric acid, D-1,2-diaminopropionicacid, D-cysteine, D-penicillamine, D-methionine, and2-aminothiazole-4-acetic acid; R⁵ is an amino acid, substituted with 0-1bonds to L_(n), independently selected at each occurrence from thegroup: glycine, L-valine, L-alanine, L-leucine, L-isoleucine,L-norleucine, L-2-aminobutyric acid, L-2-aminohexanoic acid, L-tyrosine,L-phenylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine,L-homophenylalanine, L-1-naphthylalanine, L-lysine, L-serine,L-ornithine, L-1,2-diaminobutyric acid, L-1,2-diaminopropionic acid,L-cysteine, L-penicillamine, L-methionine, and 2-aminothiazole-4-aceticacid; provided that one of R¹, R², R³, R⁴, and R⁵ in each Q issubstituted with a bond to L_(n), further provided that when R² is2-aminothiazole-4-acetic acid, K is N-methylarginine, further providedthat when R⁴ is 2-aminothiazole-4-acetic acid, K and K′ areN-methylarginine, and still further provided that when R⁵ is2-aminothiazole-4-acetic acid, K′ is N-methylarginine; d is selectedfrom 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; L_(n) is a linking group havingthe formula:(CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)—(Z)_(k)—(W)_(h)—(CR⁸R⁹)_(g″)—(W)_(h)—(CR^(8a)R^(9a))_(g″′) provided that g+h+g′+k+h′+g″+h″+g″′ is other than 0; W is independentlyselected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH,C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, (OCH₂CH₂)_(s),(CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), (CH₂CH₂CH₂O)_(t), and (aa)_(t′); aais independently at each occurrence an amino acid; Z is selected fromthe group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀ cycloalkyl substitutedwith 0-3 R¹⁰, and a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O and substitutedwith 0-3 R¹⁰; R⁶ R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹ and R^(9a) areindependently selected at each occurrence from the group: H, ═O, COOH,SO₃H, PO₃H, C₁-C₅ alkyl substituted with 0-3 R¹⁰, aryl substituted with0-3 R¹⁰, benzyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substitutedwith 0-3 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and abond to C_(h); R¹⁰ is independently selected at each occurrence from thegroup: a bond to C_(h), COOR¹¹, OH, NHR¹¹, SO₃H, PO₃H, aryl substitutedwith 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxysubstituted with 0-1 R¹², and a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-3 R¹¹; R¹¹ is independently selected at eachoccurrence from the group: H, aryl substituted with 0-1 R¹², a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-1 R¹²,C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycolsubstituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹²,cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substitutedwith 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide iscomprised of 2-10 amino acids, and a bond to C_(h); R¹² is a bond toC_(h); k is selected from 0, 1, and 2; h is selected from 0, 1, and 2;h′ is selected from 0, 1, 2, 3, 4, and 5; h″ is selected from 0, 1, 2,3, 4, and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g′is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″ is selectedfrom 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″′ is selected from 0, 1, 2,3, 4, 5, 6, 7, 8, 9, and 10; s is selected from 0, 1, 2, 3, 4, 5, 6, 7,8, 9, and 10; s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is selectedfrom 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t′ is selected from 0, 1, 2,3, 4, 5, 6, 7, 8, 9, and 10; C_(h) is a metal bonding unit having aformula selected from the group:

A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at eachoccurrence from the group N, NR¹³, NR¹³R¹⁴, S, SH, S(Pg), O, OH, PR¹³,PR¹³R¹⁴, P(O)R¹⁵R¹⁶, and a bond to L_(n); E is a bond, CH, or a spacergroup independently selected at each occurrence from the group: C₁-C₁₀alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substitutedwith 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10membered heterocyclic ring system containing 14 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷;R¹³, and R¹⁴ are each independently selected from the group: a bond toL_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substitutedwith 0-3 R¹⁷, C₁₋₁₀ cycloalkyl substituted with 0-3 R¹⁷,heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein theheterocyclo group is a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀aryl-substituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³or R¹⁴ is an electron, then the other is also an electron;alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹); R¹⁵ and R¹⁶ areeach independently selected from the group: a bond to L_(n), —OH, C₁-C₁₀alkyl substituted with 0-3 R¹⁷, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷,aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein theheterocyclo group is a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ringsystem containing 1-4 heteroatoms independently selected from N, S, andO and substituted with 0-3 R¹⁷; R¹⁷ is independently selected at eachoccurrence from the group: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN,—CO₂R¹⁸, —C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CHO, —CH₂OR¹⁸, —OC(═O)R¹⁸,—OC(═O)O^(R) ^(18a), —OR¹⁸, —OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸,—NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂, —NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a),—SO₃H, —SO₂R^(18a), —SR¹⁸, —S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂,—NHC(═S)NHR¹⁸, ═NOR¹⁸, NO₂, —C(═O)NHOR¹⁸, —C(═O)NHNR¹⁸R^(18a),—OCH₂CO₂H, 2-(1-morpholino)ethoxy, C₁-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkylmethyl, C₂-C₆ alkoxyalkyl, aryl substitutedwith 0-2 R¹⁸, and a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O; R¹⁸, R^(18a),and R¹⁹ are independently selected at each occurrence from the group: abond to L_(n), H, C₁-C₆ alkyl, phenyl, benzyl, C₁-C₆ alkoxy, halide,nitro, cyano, and trifluoromethyl; Pg is a thiol protecting group; R²⁰and R²¹ are independently selected from the group: H, C₁-C₁₀ alkyl, —CN,—CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, C₂-C₁₀ 1-alkene substituted with 0-3R²³, C₂-C₁₀ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3R²³, unsaturated 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-3 R²³, and unsaturated C₃₋₁₀ carbocycle substituted with 0-3 R²³;alternatively, R²⁰ and R²¹, taken together with the divalent carbonradical to which they are attached form:

R²² and R²³ are independently selected from the group: H, R²⁴, C₁-C₁₀alkyl substituted with 0-3 R²⁴, C₂-C₁₀ alkenyl substituted with 0-3 R²⁴,C₂-C₁₀ alkynyl substituted with 0-3 R²⁴, aryl substituted with 0-3 R²⁴,a 5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R²⁴,and C₃₋₁₀ carbocycle substituted with 0-3 R²⁴; alternatively, R²², R²³taken together form a fused aromatic or a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O; a and b indicate the positions of optional double bonds and n is0 or 1; R²⁴ is independently selected at each occurrence from the group:═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, —N(R²⁵)₃⁺, —CH₂OR²⁵, —OC(═O)R²⁵, —OC(═O)OR^(25a), —OR²⁵, —OC(═O)N(R²⁵)₂,—NR²⁶C(═O)R²⁵, —NR²⁶C(═O)OR^(25a), —NR²⁶C(═O)N(R²⁵)₂, —NR²⁶SO₂N(R²⁵)₂,—NR²⁶SO₂R^(25a), —SO₃H, —SO₂R^(25a), —SR²⁵, —S(═O)R^(25a), —SO₂N(R²⁵)₂,—N(R²⁵)₂, ═NOR²⁵, —C(═O)NHOR²⁵, —OCH₂CO₂H, and 2-(1-morpholino)ethoxy;and, R²⁵, R^(25a), and R²⁶ are each independently selected at eachoccurrence from the group: hydrogen and C₁-C₆ alkyl; and apharmaceutically acceptable salt thereof.
 28. A therapeuticradiopharmaceutical composition according to claim 27, wherein L isglycine; R¹ is an amino acid, optionally substituted with a bond toL_(n), independently selected at each occurrence from the group:L-valine, D-valine, alanine, leucine, isoleucine, norleucine,2-aminobutyric acid, tyrosine, phenylalanine, phenylglycine,cyclohexylalanine, homophenylalanine, lysine, ornithine,1,2-diaminobutyric acid, and 1,2-diaminopropionic acid; R² is an aminoacid, optionally substituted with a bond to L_(n), independentlyselected at each occurrence from the group: valine, alanine, leucine,isoleucine, norleucine, 2-aminobutyric acid, tyrosine, L-phenylalanine,D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine,cyclohexylalanine, homophenylalanine, L-1-naphthylalanine,D-1-naphthylalanine, lysine, ornithine, 1,2-diaminobutyric acid,1,2-diaminopropionic acid, and 2-aminothiazole-4-acetic acid; R³ is anamino acid, optionally substituted with a bond to L_(n), independentlyselected at each occurrence from the group: D-valine, D-alanine,D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-tyrosine, D-phenylalanine, D-phenylglycine, D-cyclohexylalanine,D-homophenylalanine, D-lysine, D-serine, D-ornithine,D-1,2-diaminobutyric acid, and D-1,2-diaminopropionic acid; R⁴ is anamino acid, optionally substituted with a bond to L_(n), independentlyselected at each occurrence from the group: D-valine, D-alanine,D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine,D-cyclohexylalanine, D-homophenylalanine, D-1-naphthylalanine, D-lysine,D-ornithine, D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid, and2-aminothiazole-4-acetic acid; R⁵ is an amino acid, optionallysubstituted with a bond to L_(n), independently selected at eachoccurrence from the group: L-valine, L-alanine, L-leucine, L-isoleucine,L-norleucine, L-2-aminobutyric acid, L-tyrosine, L-phenylalanine,L-thienylalanine, L-phenylglycine, L-cyclohexylalanine,L-homophenylalanine, L-1-naphthylalanine, L-lysine, L-ornithine,L-1,2-diaminobutyric acid, L-1,2-diaminopropionic acid, and2-aminothiazole-4-acetic acid; d is selected from 1, 2, and 3; W isindependently selected at each occurrence from the group: O, NH,NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂,(OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), and (CH₂CH₂CH₂O)_(t),Z is selected from the group: aryl substituted with 0-1 R¹⁰, C₃₋₁₀cycloalkyl substituted with 0-1 R¹⁰, and a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O and substituted with 0-1 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a),R⁹, and R^(9a) are independently selected at each occurrence from thegroup: H, ═O, COOH, SO₃H, C₁-C₅ alkyl substituted with 0-1 R¹⁰, arylsubstituted with 0-1 R¹⁰, benzyl substituted with 0-1 R¹⁰, and C₁-C₅alkoxy substituted with 0-1 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹,NHR¹¹, R¹¹, and a bond to C_(h); R¹⁰ is independently selected at eachoccurrence from the group: COOR¹¹, OH, NHR¹¹, SO₃H, aryl substitutedwith 0-1 R¹¹, a 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-1 R¹¹, C₁-C₅ alkyl substituted with 0-1 R¹², C₁-C₅ alkoxy substitutedwith 0-1 R¹², and a bond to C_(h); R¹¹ is independently selected at eachoccurrence from the group: H, aryl substituted with 0-1 R¹², a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-1 R¹²,polyalkylene glycol substituted with 0-1 R¹², carbohydrate substitutedwith 0-1 R¹², cyclodextrin substituted with 0-1 R¹² amino acidsubstituted with 0-1 R¹² and a bond to C_(h); k is 0 or 1; h is 0 or 1;h′ is 0or 1; s is selected from 0, 1, 2, 3, 4, and 5; s′ is selectedfrom 0, 1, 2, 3, 4, and 5; s″ is selected from 0, 1, 2, 3, 4, and 5; tis selected from 0, 1, 2, 3, 4, and 5; A¹, A², A³, A⁴, A⁵, A⁶, A⁷, andA⁸ are independently selected at each occurrence from the group: NR¹³,NR¹³R¹⁴, S, SH, S(Pg), OH, and a bond to L_(n); E is a bond, CH, or aspacer group independently selected at each occurrence from the group:C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷,C₃₋₁₀ cycloalkyl substituted with 0—3 R¹⁷, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-3 R¹⁷; R¹³, and R¹⁴ areeach independently selected from the group: a bond to L_(n), hydrogen,C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, a5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷,and an electron, provided that when one of R¹³ or R¹⁴ is an electron,then the other is also an electron; alternatively, R¹³ and R¹⁴ combineto form ═C(R²⁰)(R²¹); R¹⁷ is independently selected at each occurrencefrom the group: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸,—C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)O^(18a), —OR¹⁸,—OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂,—NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —S(═O)R^(18a),—SO²N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, —C(═O)NHNR¹⁸R^(18a),—OCH₂CO₂H, and 2-(1-morpholino)ethoxy; R¹⁸, R^(18a), and R¹⁹ areindependently selected at each occurrence from the group: a bond toL_(n), H, and C₁-C₆ alkyl; R²⁰ and R²¹ are independently selected fromthe group: H, C₁-C₅ alkyl, —CO₂R²⁵, C₂-C₅ 1-alkene substituted with 0-3R²³, C₂-C₅ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3R²³, and unsaturated 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O and substitutedwith 0-3 R²³; alternatively, R²⁰ and R²¹, taken together with thedivalent carbon radical to which they are attached form:

R²² and R²³ are independently selected from the group: H, and R²⁴;alternatively, R²², R²³ taken together form a fused aromatic or a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O; R²⁴ is independently selectedat each occurrence from the group: —CO₂R²⁵, —C(═O)N(R²⁵)₂, —CH₂OR²⁵,—OC(═O)R²⁵, —OR²⁵, —SO₃H, —N(R²⁵)₂, and —OCH₂CO₂H; and, R²⁵ isindependently selected at each occurrence from the group: H and C₁-C₃alkyl.
 29. A therapeutic radiopharmaceutical composition according toclaim 28, wherein: Q is a peptide selected from the group:

R¹ is L-valine, D-valine, D-lysine optionally substituted on the ε aminogroup with a bond to L_(n) or L-lysine optionally substituted on the εamino group with a bond to L_(n); R² is L-phenylalanine,D-phenylalanine, D-1-naphthylalanine, 2-aminothiazole-4-acetic acid,L-lysine optionally substituted on the ε amino group with a bond toL_(n) or tyrosine, the tyrosine optionally substituted on the hydroxygroup with a bond to L_(n); R³ is D-valine, D-phenylalanine, or L-lysineoptionally substituted on the ε amino group with a bond to L_(n); R⁴ isD-phenylalanine, D-tyrosine substituted on the hydroxy group with a bondto L_(n), or L-lysine optionally substituted on the ε amino group with abond to L_(n); provided that one of R¹ and R² in each Q is substitutedwith a bond to L_(n), and further provided that when R² is2-aminothiazole-4-acetic acid, K is N-methylarginine; d is 1 or 2; W isindependently selected at each occurrence from the group: NHC(═O),C(═O)NH, C(═O), (CH₂CH₂O)_(s′), and (CH₂CH₂CH₂O)_(t); R⁶, R^(6a), R⁷,R^(7a), R⁸, R^(8a), R⁹, and R^(9a) are independently selected at eachoccurrence from the group: H, NHC(═O)R¹¹, and a bond to C_(h); k is 0;h″ is selected from 0, 1, 2, and 3; g is selected from 0, 1, 2, 3, 4,and 5; g′ is selected from 0, 1, 2, 3, 4, and 5; g″ is selected from 0,1, 2, 3, 4, and 5; g″′ is selected from 0, 1, 2, 3, 4, and 5; s′ is 1 or2; t is 1 or 2; C_(h) is

A¹ is selected from the group: OH, and a bond to L_(n); A², A⁴, and A⁶are each N; A³, A⁵, and A⁸ are each OH; A⁷ is a bond to L_(n) or NH-bondto L_(n); E is a C₂ alkyl substituted with 0-1 R¹⁷; R¹⁷ is ═O;alternatively, C_(h) is

A¹ is NH₂ or N═C(R²⁰)(R²¹); E is a bond; A² is NHR¹³; R¹³ is aheterocycle substituted with R¹⁷, the heterocycle being selected frompyridine and pyrimidine; R¹⁷ is selected from a bond to L_(n),C(═O)NHR¹⁸, and C(═O)R¹⁸;  R¹⁸ is a bond to L_(n);  R²⁴ is selected fromthe group: —CO₂R²⁵, —OR²⁵, —SO₃H, and —N(R²⁵)₂; R²⁵ is independentlyselected at each occurrence from the group: hydrogen and methyl;

alternatively, C_(h) is A¹, A², A³, and A⁴ are each N; A⁵, A⁶, and A⁸are each OH; A⁷ is a bond to L_(n); E is a C₂ alkyl substituted with 0-1R¹⁷; and, R¹⁷ is ═O.
 30. A therapeutic radiopharmaceutical compositionaccording to claim 28, wherein the compound is selected from the groupconsisting of: (a)cyclo{Arg-Gly-Asp-D-Tyr(N[2-[[[5-[carbonyl-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (b)cyclo{Arg-Gly-Asp-D-Tyr((N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-18-amino-14-aza-4,7,10-oxy-15-oxo-octadecoyl)-3-aminopropyl)-Val};(c) [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp})-cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp};(d)cyclo(Arg-Gly-Asp-D-Tyr-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (e)cyclo{Arg-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (f)[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};(g) [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Phe-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};(h)cyclo{Arg-Gly-Asp-D-Nal-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (i)[2-[[[5-[carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal};(j)cyclo{Arg-Gly-Asp-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Val}; (k)[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-D-Val-Arg-Gly-Asp})-cyclo{Lys-D-Val-Arg-Gly-Asp};(l){cyclo(Arg-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; (m)cyclo{D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Phe-D-Asp-Gly-Arg}; (n)[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg};(o)cyclo{D-Phe-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Asp-Gly-Arg }; (p)cyclo{N-Me-Arg-Gly-Asp-ATA-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (q)cyclo{Cit-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (r)2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};(s) cyclo{Arg-Gly-Asp-D-Phe-Lys(DTPA)}; (t) cyclo{Arg-Gly-Asp-D-Phe-Lys)₂(DTPA); (u) cyclo{Arg-Gly-Asp-D-Tyr(N-DTPA-3-aminopropyl)-Val}; (v)cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (w)cyclo{Lys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (x)cyclo{Cys(2-aminoethyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (y)cyclo{HomoLys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (z)cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (aa)cyclo{Dap(b-(2-benzimidazolylacetyl))-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (bb)cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (cc)cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (dd)cyclo{Lys-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; (ee)cyclo{Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; and, (ff)cyclo{Orn(d-N-2-Imidazolinyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; or a pharmaceutically acceptable saltform thereof.
 31. A therapeutic radiopharmaceutical compositionaccording to claim 27, which further comprises one or more ancillaryligands and a reducing agent.
 32. A therapeutic radiopharmaceuticalcomposition according to claim 31, wherein the ancillary ligands aretricine and TPPTS.
 33. A therapeutic radiopharmaceutical compositionaccording to claim 32, wherein the reducing agent is tin(II).
 34. Amethod of treating cancer according to claim 11, wherein the compound isof the formula: (Q)d—L_(n)—C_(h) or (Q)_(d)—L_(n)—(C_(h))_(′) wherein, Qis a peptide independently selected from the group:

K is an L-amino acid independently selected at each occurrence from thegroup: arginine, citrulline, N-methylarginine, lysine, homolysine,2-aminoethylcysteine, δ-N-2-imidazolinylornithine,δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid; K′ is a D-amino acidindependently selected at each occurrence from the group: arginine,citrulline, N-methylarginine, lysine, homolysine, 2-aminoethylcysteine,δ-N-2-imidazolinylornithine, δ-N-benzylcarbamoylornithine, andβ-2-benzimidazolylacetyl-1,2-diaminopropionic acid; L is independentlyselected at each occurrence from the group: glycine, L-alanine, andD-alanine; M is L-aspartic acid; M′ is D-aspartic acid; R¹ is an aminoacid substituted with 0-1 bonds to L_(n), independently selected at eachoccurrence from the group: glycine, L-valine, D-valine, alanine,leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoicacid, tyrosine, phenylalanine, thienylalanine, phenylglycine,cyclohexylalanine, homophenylalanine, 1-naphthylalanine, lysine, serine,ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine,penicillamine, and methionine; R² is an amino acid, substituted with 0-1bonds to L_(n), independently selected at each occurrence from thegroup: glycine, valine, alanine, leucine, isoleucine, norleucine,2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, L-phenylalanine,D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine,cyclohexylalanine, homophenylalanine, L-1-naphthylalanine,D-1-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid,1,2-diaminopropionic acid, cysteine, penicillamine, methionine, and2-aminothiazole-4-acetic acid; R³ is an amino acid, substituted with 0-1bonds to L_(n), independently selected at each occurrence from thegroup: glycine, D-valine, D-alanine, D-leucine, D-isoleucine,D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine,D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine,D-homophenylalanine, D-1-naphthylalanine, D-lysine, D-serine,D-ornithine, D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid,D-cysteine, D-penicillamine, and D-methionine; R⁴ is an amino acid,substituted with 0-1 bonds to L_(n), independently selected at eachoccurrence from the group: glycine, D-valine, D-alanine, D-leucine,D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoicacid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine,D-cyclohexylalanine, D-homophenylalanine, D-1-naphthylalanine, D-lysine,D-serine, D-ornithine, D-1,2-diaminobutyric acid, D-1,2-diaminopropionicacid, D-cysteine, D-penicillamine, D-methionine, and2-aminothiazole-4-acetic acid; R⁵ is an amino acid, substituted with 0-1bonds to L_(n), independently selected at each occurrence from thegroup: glycine, L-valine, L-alanine, L-leucine, L-isoleucine,L-norleucine, L-2-aminobutyric acid, L-2-aminohexanoic acid, L-tyrosine,L-phenylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine,L-homophenylalanine, L-1-naphthylalanine, L-lysine, L-serine,L-ornithine, L-1,2-diaminobutyric acid, L-1,2-diaminopropionic acid,L-cysteine, L-penicillamine, L-methionine, and 2-aminothiazole-4-aceticacid; provided that one of R¹, R², R³, R⁴, and R⁵ in each Q issubstituted with a bond to L_(n), further provided that when R² is2-aminothiazole-4-acetic acid, K is N-methylarginine, further providedthat when R⁴ is 2-aminothiazole-4-acetic acid, K and K′ areN-methylarginine, and still further provided that when R⁵ is2-aminothiazole-4-acetic acid, K′ is N-methylarginine; d is selectedfrom 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; L_(n) is a linking group havingthe formula:(CR⁶R⁷)_(g)′—(W)_(h)′—(CR^(6a)R^(7a))_(g)—(Z)_(k)—(W)_(h)—(CR⁸R⁹)_(g″)—(W)_(h″)—(CR^(8a)R^(9a))_(″′) provided that g+h+g′+k+h′+g″+h″+g″′ is other than 0; W is independentlyselected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH,C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, (OCH₂CH₂)_(s),(CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), (CH₂CH₂CH₂O)_(t), and (aa)_(t′); aais independently at each occurrence an amino acid; Z is selected fromthe group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀ cycloalkyl substitutedwith 0-3 R¹⁰, and a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O and substitutedwith 0-3 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹ and R^(9a) areindependently selected at each occurrence from the group: H, ═O, COOH,SO₃H, PO₃H, C₁-C₅ alkyl substituted with 0-3 R¹⁰, aryl substituted with0-3 R¹⁰, benzyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substitutedwith 0-3 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and abond to C_(h); R¹⁰ is independently selected at each occurrence from thegroup: a bond to C_(h), COOR¹¹, OH, NHR¹¹, SO₃H, PO₃H, aryl substitutedwith 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxysubstituted with 0-1 R¹², and a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-3 R¹¹; R¹¹ is independently selected at eachoccurrence from the group: H, aryl substituted with 0-1 R¹², a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-1 R¹²,C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycolsubstituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹²,cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substitutedwith 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide iscomprised of 2-10 amino acids, and a bond to C_(h); R¹² is a bond toC_(h); k is selected from 0, 1, and 2; h is selected from 0, 1, and 2;h′ is selected from 0 1, 2, 3, 4, and 5; h″ is selected from 0, 1, 2, 3,4, and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g′ isselected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″ is selected from0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″′ is selected from 0, 1, 2, 3,4, 5, 6, 7, 8, 9, and 10; s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8,9, and 10; s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s″is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is selectedfrom 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t′ is selected from 0, 1, 2,3, 4, 5, 6, 7, 8, 9, and 10; C_(h) is a metal bonding unit having aformula selected from the group:

A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at eachoccurrence from the group N, NR¹³, NR¹³R¹⁴, S, SH, S(Pg), O, OH, PR¹³,PR¹³R¹⁴, P(O)R¹⁵R¹⁶, and a bond to L_(n); E is a bond, CH, or a spacergroup independently selected at each occurrence from the group: C₁-C₁₀alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substitutedwith 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷;R¹³, and R¹⁴ are each independently selected from the group: a bond toL_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substitutedwith 0-3 R¹⁷, C₁₋₁₀ cycloalkyl substituted with 0-3 R¹⁷,heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein theheterocyclo group is a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀aryl-substituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³or R¹⁴ is an electron, then the other is also an electron;alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹); R¹⁵ and R¹⁶ areeach independently selected from the group: a bond to L_(n), —OH, C₁-C₁₀alkyl substituted with 0-3 R¹⁷, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷,aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein theheterocyclo group is a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ringsystem containing 1-4 heteroatoms independently selected from N, S, andO and substituted with 0-3 R¹⁷; R¹⁷ is independently selected at eachoccurrence from the group: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN,—CO₂R¹⁸, —C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CHO, —CH₂OR¹⁸, —OC(═O)R¹⁸,—OC(═O)OR^(18a), —OR¹⁸, —OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸,—NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂, —NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a),—SO₃H, —SO₂R^(18a), —SR¹⁸, —S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂,—NHC(═S)NHR¹⁸, ═NOR¹⁸, NO₂, —C(═O)NHOR¹⁸, —C(═O)NHNR¹⁸R^(18a),—OCH₂CO₂H, 2-(1-morpholino)ethoxy, C₁-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkylmethyl, C₂-C₆ alkoxyalkyl, aryl substitutedwith 0-2 R¹⁸, and a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O; R¹⁸, R^(18a),and R¹⁹ are independently selected at each occurrence from the group: abond to L_(n), H, C₁-C₆ alkyl, phenyl, benzyl, C₁-C₆ alkoxy, halide,nitro, cyano, and trifluoromethyl; Pg is a thiol protecting group; R²⁰and R²¹ are independently selected from the group: H, C₁-C₁₀ alkyl, —CN,—CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, C₂-C₁₀ 1-alkene substituted with 0-3R²³, C₂-C₁₀ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3R²³, unsaturated 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-3 R²³, and unsaturated C₃₋₁₀ carbocycle substituted with 0-3 R²³;alternatively, R²⁰ and R²¹, taken together with the divalent carbonradical to which they are attached form:

R²² and R²³ are independently selected from the group: H, R²⁴, C₁-C₁₀alkyl substituted with 0-3 R²⁴, C₂-C₁₀ alkenyl substituted with 0-3 R²⁴,C₂-C₁₀ alkynyl substituted with 0-3 R²⁴, aryl substituted with 0-3 R²⁴,a 5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R²⁴,and C₃₋₁₀ carbocycle substituted with 0-3 R²⁴; alternatively, R²², R²³taken together form a fused aromatic or a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O; a and b indicate the positions of optional double bonds and n is0 or 1; R²⁴ is independently selected at each occurrence from the group:═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, —N(R²⁵)₃⁺, —CH₂OR²⁵, —OC(═O)R²⁵, —OC(═O)OR^(25a), —OR²⁵, —OC(═O)N(R²⁵)₂,—NR²⁶C(═O)R²⁵, NR²⁶C(═O)OR^(25a), —NR²⁶C(═O)N(R²⁵)₂, —NR²⁶SO₂N(R²⁵)₂,—NR²⁶SO₂R^(25a), —SO₃H, —SO₂R^(25a), —SR²⁵, —S(═O)R^(25a), —SO₂N(R²⁵)₂,—N(R²⁵)₂, ═NOR²⁵, —C(═O)NHOR²⁵, —OCH₂CO₂H, and 2-(1-morpholino)ethoxy;and, R²⁵, R^(25a), and R²⁶ are each independently selected at eachoccurrence from the group: hydrogen and C₁-C₆ alkyl; and apharmaceutically acceptable salt thereof.
 35. A method of treatingcancer according to claim 34, wherein L is glycine; R¹ is an amino acid,optionally substituted with a bond to L_(n), independently selected ateach occurrence from the group: L-valine, D-valine, alanine, leucine,isoleucine, norleucine, 2-aminobutyric acid, tyrosine, phenylalanine,phenylglycine, cyclohexylalanine, homophenylalanine, lysine, ornithine,1,2-diaminobutyric acid, and 1,2-diaminopropionic acid; R² is an aminoacid, optionally substituted with a bond to L_(n), independentlyselected at each occurrence from the group: valine, alanine, leucine,isoleucine, norleucine, 2-aminobutyric acid, tyrosine, L-phenylalanine,D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine,cyclohexylalanine, homophenylalanine, L-1-naphthylalanine,D-1-naphthylalanine, lysine, ornithine, 1,2-diaminobutyric acid,1,2-diaminopropionic acid, and 2-aminothiazole-4-acetic acid; R³ is anamino acid, optionally substituted with a bond to L_(n), independentlyselected at each occurrence from the group: D-valine, D-alanine,D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-tyrosine, D-phenylalanine, D-phenylglycine, D-cyclohexylalanine,D-homophenylalanine, D-lysine, D-serine, D-ornithine,D-1,2-diaminobutyric acid, and D-1,2-diaminopropionic acid; R⁴ is anamino acid, optionally substituted with a bond to L_(n), independentlyselected at each occurrence from the group: D-valine, D-alanine,D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid,D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine,D-cyclohexylalanine, D-homophenylalanine, D-1-naphthylalanine, D-lysine,D-ornithine, D-1,2-diaminobutyric acid, D-1,2-diaminopropionic acid, and2-aminothiazole-4-acetic acid; R⁵ is an amino acid, optionallysubstituted with a bond to L_(n), independently selected at eachoccurrence from the group: L-valine, L-alanine, L-leucine, L-isoleucine,L-norleucine, L-2-aminobutyric acid, L-tyrosine, L-phenylalanine,L-thienylalanine, L-phenylglycine, L-cyclohexylalanine,L-homophenylalanine, L-1-naphthylalanine, L-lysine, L-ornithine,L-1,2-diaminobutyric acid, L-1,2-diaminopropionic acid, and2-aminothiazole-4-acetic acid; d is selected from 1, 2, and 3; W isindependently selected at each occurrence from the group: O, NH,NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂,(OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), and (CH₂CH₂CH₂O)_(t),Z is selected from the group: aryl substituted with 0-1 R¹⁰, C₃₋₁₀cycloalkyl substituted with 0-1 R¹⁰, and a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O and substituted with 0-1 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a),R⁹, and R^(9a) are independently selected at each occurrence from thegroup: H, ═O, COOH, SO₃H, C₁-C₅ alkyl substituted with 0-1 R¹⁰, arylsubstituted with 0-1 R¹⁰, benzyl substituted with 0-1 R¹⁰, and C₁-C₅alkoxy substituted with 0-1 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹,NHR¹¹, R¹¹, and a bond to C_(h); R¹⁰ is independently selected at eachoccurrence from the group: COOR¹¹, OH, NHR¹¹, SO₃H, aryl substitutedwith 0-1 R¹¹, a 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-1 R¹¹, C₁-C₅ alkyl substituted with 0-1 R¹², C₁-C₅ alkoxy substitutedwith 0-1 R¹², and a bond to C_(h); R¹¹ is independently selected at eachoccurrence from the group: H, aryl substituted with 0-1 R¹², a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-1 R¹²,polyalkylene glycol substituted with 0-1 R¹², carbohydrate substitutedwith 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acidsubstituted with 0-1 R¹², and a bond to C_(h); k is 0 or 1; h is 0 or 1;h′ is 0or 1; s is selected from 0, 1, 2, 3, 4, and 5; s′ is selectedfrom 0, 1, 2, 3, 4, and 5; s″ is selected from 0, 1, 2, 3, 4, and 5; tis selected from 0, 1, 2, 3, 4, and 5; A¹, A², A³, A⁴, A⁵, A⁶, A⁷, andA⁸ are independently selected at each occurrence from the group: NR¹³,NR¹³R¹⁴, S, SH, S(Pg), OH, and a bond to L_(n); E is a bond, CH, or aspacer group independently selected at each occurrence from the group:C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷,C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-3 R¹⁷; R¹³, and R¹⁴ areeach independently selected from the group: a bond to L_(n), hydrogen,C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, a5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷,and an electron, provided that when one of R¹³ or R¹⁴ is an electron,then the other is also an electron; alternatively, R¹³ and R¹⁴ combineto form ═C(R²⁰)(R²¹); R¹⁷ is independently selected at each occurrencefrom the group: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸,—C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸,—OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂,—NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO²R^(18a), —S(═O)R^(18a),—SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, —C(═O)NHNR¹⁸R^(18a),—OCH₂CO₂H, and 2-(1-morpholino)ethoxy; R¹⁸, R^(18a), and R¹⁹ areindependently selected at each occurrence from the group: a bond toL_(n), H, and C₁-C₆ alkyl; R²⁰ and R²¹ are independently selected fromthe group: H, C₁-C₅ alkyl, —CO₂R²⁵, C₂-C₅ 1-alkene substituted with 0-3R²³, C₂-C₅ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3R²³, and unsaturated 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O and substitutedwith 0-3 R²³; alternatively, R²⁰ and R²¹, taken together with thedivalent carbon radical to which they are attached form:

R²² and R²³ are independently selected from the group: H, and R²⁴;alternatively, R²², R²³ taken together form a fused aromatic or a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O; R²⁴ is independently selectedat each occurrence from the group: —CO₂R²⁵, —C(═O)N(R²⁵)₂, —CH₂OR²⁵,—OC(═O)R²⁵, —OR²⁵, —SO₃H, —N(R²⁵)₂, and —OCH₂CO₂H; and, R²⁵ isindependently selected at each occurrence from the group: H and C₁-C₃alkyl.
 36. A method of treating cancer according to claim 35, wherein: Qis a peptide selected from the group:

R¹ is L-valine, D-valine, D-lysine optionally substituted on the ε aminogroup with a bond to L_(n) or L-lysine optionally substituted on the εamino group with a bond to L_(n); R² is L-phenylalanine,D-phenylalanine, D-1-naphthylalanine, 2-aminothiazole-4-acetic acid,L-lysine optionally substituted on the ε amino group with a bond toL_(n) or tyrosine, the tyrosine optionally substituted on the hydroxygroup with a bond to L_(n); R³ is D-valine, D-phenylalanine, or L-lysineoptionally substituted on the ε amino group with a bond to L_(n); R⁴ isD-phenylalanine, D-tyrosine substituted on the hydroxy group with a bondto L_(n), or L-lysine optionally substituted on the ε amino group with abond to L_(n); provided that one of R¹ and R² in each Q is substitutedwith a bond to L_(n), and further provided that when R² is2-aminothiazole-4-acetic acid, K is N-methylarginine; d is 1 or 2; W isindependently selected at each occurrence from the group: NHC(═O),C(═O)NH, C(═O), (CH₂CH₂O)_(s′), and (CH₂CH₂CH₂O)_(t); R⁶, R^(6a), R⁷,R^(7a), R⁸, R^(8a), R⁹, and R^(9a) are independently selected at eachoccurrence from the group: H, NHC(═O)R¹¹, and a bond to C_(h); k is 0;h″ is selected from 0, 1, 2, and 3; g is selected from 0, 1, 2, 3, 4,and 5; g′ is selected from 0, 1, 2, 3, 4, and 5; g″ is selected from 0,1, 2, 3, 4, and 5; g″′ is selected from 0, 1, 2, 3, 4, and 5; s′ is 1 or2; t is 1 or 2;  C_(h) is

A¹ is selected from the group: OH, and a bond to L_(n); A², A⁴, and A⁶are each N; A³, A⁵, and A⁸ are each OH; A⁷ is a bond to L_(n) or NH-bondto L_(n); E is a C₂ alkyl substituted with 0-1 R¹⁷; R¹⁷ is ═O; alternatively, C_(h) is

A¹ is NH₂ or N═C(R²⁰)(R²¹); E is a bond; A² is NHR¹³;  R¹³ is aheterocycle substituted with R¹⁷, the heterocycle being selected frompyridine and pyrimidine; R¹⁷ is selected from a bond to L_(n),C(═O)NHR¹⁸, and C(═O)R¹⁸; R¹⁸ is a bond to L_(n); R²⁴ is selected fromthe group: —CO₂R²⁵, —OR²⁵, —SO₃H, and —N(R²⁵)₂;  R²⁵ is independentlyselected at each occurrence from the group: hydrogen and methyl;

 alternatively, C_(h) is A¹, A², A³, and A⁴ are each N; A⁵, A⁶, and A⁸are each OH; A⁷ is a bond to L_(n); E is a C₂ alkyl substituted with 0-1R¹⁷; and, R¹⁷ is ═O.
 37. A method of treating cancer according to claim34, wherein the compound is selected from the group consisting of: (a)cyclo{Arg-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (b)cyclo{Arg-Gly-Asp-D-Tyr((N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-18-amino-14-aza-4,7,10-oxy-15-oxo-octadecoyl)-3-aminopropyl)-Val};(c) [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Tyr(3aminopropyl)-Val-Arg-Gly-Asp})-cyclo{D-Tyr(3-aminopropyl)-Val-Arg-Gly-Asp};(d)cyclo(Arg-Gly-Asp-D-Tyr-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (e)cyclo{Arg-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (f)[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};(g) [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Phe-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};(h)cyclo{Arg-Gly-Asp-D-Nal-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (i)[2-[[[5-[carbonyl]-2-pyridinyl]-hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-Arg-Gly-Asp-D-Nal})-cyclo{Lys-Arg-Gly-Asp-D-Nal};(j)cyclo{Arg-Gly-Asp-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Val}; (k)[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{Lys-D-Val-Arg-Gly-Asp})-cyclo{Lys-D-Val-Arg-Gly-Asp};(l){cyclo(Arg-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; (m)cyclo{D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Phe-D-Asp-Gly-Arg}; (n)[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-Glu(cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg})-cyclo{D-Lys-D-Phe-D-Asp-Gly-Arg};(o)cyclo{D-Phe-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])-D-Asp-Gly-Arg}; (p)cyclo{N-Me-Arg-Gly-Asp-ATA-D-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (q)cyclo{Cit-Gly-Asp-D-Phe-Lys([2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (r)2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-Glu(cyclo{Lys-Arg-Gly-Asp-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe};(s) cyclo{Arg-Gly-Asp-D-Phe-Lys(DTPA)}; (t)cyclo{Arg-Gly-Asp-D-Phe-Lys}₂(DTPA); (u)Cyclo{Arg-Gly-Asp-D-Tyr(N-DTPA-3-aminopropyl)-Val}; (v)cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (w)cyclo{Lys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (x)cyclo{Cys(2-aminoethyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val }; (y)cyclo{HomoLys-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (z)cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (aa)cyclo{Dap(b-(2-benzimidazolylacetyl))-Gly-Asp-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-Val}; (bb)cyclo{Orn(d-N-2-Imidazolinyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (cc)cyclo{Orn(d-N-Benzylcarbamoyl)-Gly-Asp-D-Phe-Lys(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid])}; (dd)cyclo{Lys-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; (ee)cyclo{Orn(d-N-Benzylcarbamoyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; and, (ff)cyclo{Orn(d-N-2-Imidazolinyl)-D-Val-D-Tyr(N-[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonicacid]-3-aminopropyl)-D-Asp-Gly}; or a pharmaceutically acceptable saltform thereof.